Cyclopenta[c]pyrrole derivatives

ABSTRACT

2,4,5,6-Tetrahydrocyclopenta[c]pyrrole-4-carboxyamide and 4-thiocarboxamide derivatives useful as anti-secretory and anti-ulcer agents are prepared by hydrolysis or thiohydrolysis of the corresponding 2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitriles or, in the case of the thiocarboxamides, by reaction of the 4-carboxamide with phosphorus pentasulfide.

RELATED APPLICATIONS

This is a division of our prior, copending application Ser. No. 558,807,filed Mar. 17, 1975, now U.S. Pat. No. 4,008,250, patented Feb. 15,1977, which in turn is a continuation-in-part of our prior, copendingapplication Ser. No. 346,005, filed Mar. 29, 1973, now U.S. Pat. No.3,928,380, patented Dec. 23, 1975.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carboxamides andthiocarboxamides useful as anti-secretory and anti-ulcer agents.

2. Description of the Prior Art

Although the 2,4,5,6-tetrahydrocyclopenta[c]pyrrole ring system is known(see for example Volz et al., Tetrahedron Letters 47, 4111-14 (1969) whodisclose 1,3-dimethyl- and1,2,3-trimethyl-4-oxo-2,4,5,6-tetrahydrocyclopenta[c]pyrrole and Bergeret al., J. Org. Chem. 35, 3122 (1970) who disclose1,3-dimethyl-4-oxo-2,4,5,6-tetrahydrocyclopenta[c]pyrrole), derivativesof such ring system having exocyclic functions, other than methyl groupsat the 1-, 2- and 3-positions, have not been previously known.Furthermore the aforementioned prior art species are prepared bylaborious multi-step synthetic methods and are not known to have anyutility except as laboratory curiosities.

SUMMARY OF THE INVENTION

In one of its composition of matter aspects, the invention relates tocertain 1,3-di-R₆ -2-R₇ -4-R₃ -6-R₄ -6-R₅-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carboxamides andthiocarboxamides where R₃, R₄, R₅, R₆ and R₇ are hydrogen, lower-alkylor other organic groups more specifically defined hereinafter, which areuseful as anti-secretory and anti-ulcer agents.

In a second composition of matter aspect, the invention relates tocertain 1,3-di-R₆ -2-R₇ -4-R₃ -6-R₄ -6-R₅-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitriles which are usefulas intermediates for the preparation of the corresponding 4-carboxamidefinal products.

In one of its process aspects, the invention relates to a process forpreparing certain 1,3-di-R₆ -2-R₇ -4-R₃ -6-R₄ -6-R₅-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carboxamides comprisinghydrolyzing the corresponding 4-carbonitriles.

In another of its process aspects, the invention relates to a processfor preparing certain 1,3-di-R₆ -2-R₇ -4-R₃ -6-R₄ -6-R₅-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-(N-R₁ -N-R₂)-carboxamidescomprising reacting the corresponding compounds where one or both of R₁and R₂ are hydrogen with a strong base and reacting the resulting saltwith an alkylating agent.

In another of its process aspects, the invention relates to a processfor preparing certain 1,3-di-R₆-4,6,6-trimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrilescomprising reacting an alkanedione, R₆ -CO-CH₂ CH₂ -CO-R₆, with2-amino-2-methylpropionitrile in an acid medium.

In another of its process aspects, the invention relates to a processfor preparing certain 1,3-di-R₆ -2-R₇-4,6,6-trimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrilescomprising reacting a 1-R₇ -2,5-di-R₆ -substituted-pyrrole with2-amino-2-methylpropionitrile.

In another of its process aspects, the invention relates to a processfor preparing certain 1,3-di-R₆ -2-R₇-4,6,6-trimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrilescomprising reacting a 1-R₇ -2,5-di-R₆ -substituted-pyrrole with excessacetone in the presence of a mineral acid and reacting the resulting3,3,3',3'-tetramethyl-4,4',6,6'-tetra-R₆-1,1'-spirobis(cyclopenta[4,5-c]pyrrole) with a source of ammonia and asource of cyanide ions in the presence of glacial acetic acid or with anequimolar amount of acetone.

In another of its process aspects, the invention relates to a processfor preparing certain 1,3-diformyl-2-R₇ -4-R₃ -6-R₄ -6-R₅-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitriles comprisingreacting the corresponding 1,3 -dimethyl compounds with four moles ofsulfuryl chloride and hydrolyzing the resulting 1,3-bis(dichloromethyl)compounds.

In another of its process aspects, the invention relates to a processfor preparing certain 2-R₇ -4-R₃ -6-R₄ -6-R₅-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitriles unsubstituted atthe 1- and 3-positions comprising decarbonylation of the corresponding1,3-diformyl compound over a palladium-on-charcoal catalyst in an inertorganic solvent.

In another of its process aspects, the invention relates to a processfor preparing certain 1,3-di-R₆-4,6,6-trimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrilescomprising reacting an alkanedione, R₆ -CO-CH₂ CH₂ -CO-R₆, with acetone,a source of ammonia and a source of cyanide ions in an acid medium.

In another of its process aspects, the invention relates to a processfor preparing certain 1,3-di-R₆ -2-R₇-4,6,6-trimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrilescomprising reacting a 1-R₇ -2,5-di-R₆ -substituted-pyrrole with acetone,a source of ammonia and a source of cyanide ions in an acid medium.

In another of its process aspects, the invention relates to a processfor preparing certain 1,3-di-R₆ -2-R₇ -4-R₃ -6-R₄ -6-R₅-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carboxamides comprisingoxidizing a corresponding 4-aldiminde with oxygen.

In another of its process aspects, the invention relates to a processfor preparing certain 1,3-di-R₆ -2-R₇ -4-R₃ -6-R₄ -6-R₅-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carboxamides comprisingthermal or photochemical decomposition of a corresponding 1,3-di-R₆-2-R₇ -4-R₃ -6-R₄ -6-R₅-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-(3-oxaziridine).

In another of its process aspects, the invention relates to a processfor preparing certain 1,3-di-R₆ -2-R₇ -4-R₃ -6-R₄ -6-R₅-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carboxamides comprisingoxidizing a corresponding 4-carbonitrile with hydrogen peroxide in abasic medium and decomposing the resulting perimidate by heating thereaction medium.

In another of its process aspects, the invention relates to a processfor preparing certain 1,3-di-R₆ -2-R₇-4,6,6-trimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrilescomprising reacting with cyanide in glacial acetic acid a 1,3-di-R₆-2-R₇ -4,4,6,6-tetramethyl-5,6-dihydro-1H-furo[3,4-c]pyrrole.

In another of its process aspects, the invention relates to a processfor preparing certain 1-methyl-3-formyl-(and 1-formyl-3-methyl)-2-R₇-4-R₃ -6-R₄ -6-R₅ -2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carboxamidescomprising oxidizing with oxygen a corresponding 1,3-dimethyl compound.

DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS

More specifically, the invention relates to2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carboxamides and4-thiocarboxamides, which are useful as anti-secretory and anti-ulceragents and which have the Formula I: ##STR1## where X is O or S; R₁ ishydrogen, lower-alkyl, di-lower-alkylamino-lower-alkyl,morpholino-lower-alkyl, 1-pyrrolidyl-loweralkyl or1-piperidyl-lower-alkyl; R₂ is hydrogen or lower-alkyl, or the group##STR2## can represent a 1-imidazolyl group; each of R₃, R₄ and R₅ ishydrogen or methyl; each R₆ group is the same or different hydrogen,formyl (CHO) and lower-alkane-1,3-diol ketals thereof,phenyl-lower-alkyl, carboxy, carbo-lower-alkoxy, lower-alkyl, or a groupof the formula: ##STR3## where R₈ is hydrogen, lower-alkyl,lower-alkenyl, lower-alkynyl, phenyl or phenyl-lower-alkyl; R₉ ishydrogen, cyano (CN), lower-alkyl, lower-alkenyl, lower-alkynyl, phenyl,phenyl-lower-alkyl, carboxy, carbo-lower-alkoxy, carbamyl (CONH₂),aminomethyl (CH₂ NH₂), lower-alkanoyl, or trichloromethyl; R₁₀ ishydrogen, benzoyl, lower-alkanoyl, carboxy-lower-alkanoyl (and ammoniumsalts thereof) or lower-alkyl, R₁₀ being other than hydrogen only wheneither one or both of R₈ and R₉ are hydrogen and R₈ being cyano onlywhen R₁₀ is hydrogen; and R₇ is hydrogen, lower-alkyl, halo-lower-alkyl,lower-alkenyl, lower-alkynyl, di-lower-alkyl-amino-lower-alkyl,morpholino-lower-alkyl, 1-pyrrolidyl-lower-alkyl,1-piperidyl-lower-alkyl, carbo-lower-alkoxy-lower-alkyl,carboxy-lower-alkyl, carboxamido-lower-alkyl,thiocarboxamido-lower-alkyl, lower-alkoxyl-lower-alkyl,hydroxy-lower-alkyl, lower-alkylthio-lower-alkyl, cycloalkyl,cycloalkyl-lower-alkyl, 2- or 3-pyridyl, phenyl, phenyl-lower-alkyl,thienyl, 9-acridinyl, 4-(2,1,3-benzothiadiazolyl), 2-benzothiazolyl,3-carbazolyl, 2-benzoxazolyl, 2- or 6-purinyl, 2-pyrazinyl,4-pyrimidinyl, 2-thiazolyl, 3-pyrazolyl, 2- or 6-pyrimidinyl,2-benzimidazolyl, 2-benzothiazolyl, 5-, 6- or 7-indazolyl,5-isoquinolinyl, 3-pyridazinyl, 2-thiadiazolyl, 5-tetrazolyl,2-thiazolinyl, 3-(1,2,4-triazinyl), 3-(1,2,4-triazolyl), ordivalent-lower-alkylene having its valences on different carbon atomsand joining two of the 2,4,5,6-tetrahydrocyclopenta[c]pyrrole moietiestogether, and wherein the phenyl or phenyl-lower-alkyl groups can befurther substituted in the phenyl nucleus by a single methylenedioxy orfrom one to three members of the group consisting of lower-alkyl,lower-alkoxy, halogen (including fluorine, bromine and chlorine),hydroxy, trifluoromethyl, lower-alkanoylamino, amino,di-lower-alkylamino, carboxyl, carboxamido, carbo-lower-alkoxy,lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, nitro andsulfamoyl.

Preferred compounds with the ambit of Formula I are those where X is O;each of R₁ and R₂ is hydrogen or lower-alkyl; each of R₃, R₄ and R₅ ishydrogen or methyl; both R₆ groups are lower-alkyl; and R₇ islower-alkyl or phenyl and also the compounds of formula I where X is O;R₁ and R₂ are each hydrogen; R₃, R₄ and R₅ are each methyl; one R₆ ishydrogen, lower-alkyl or hydroxymethyl and the other is hydrogen,lower-alkyl or the group: ##STR4## where R₈ is hydrogen, lower-alkyl,lower-alkenyl, or lower-alkynyl; and R₇ is phenyl (orsubstituted-phenyl), both of which preferred groups are represented bythe formula: ##STR5##

As used herein the terms "lower-alkyl" and "lower-alkoxy" meansaturated, monovalent, aliphatic radicals, including straight orbranched-chain radicals, of from one to four carbon atoms as illustratedby, but not limited to, methyl, ethyl, propyl, isopropyl, butyl,sec.-butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, and the like.

As used herein the term "cycloalkyl" means saturated carbocyclic groupscontaining from three to six ring carbon atoms and having a total offive to ten carbon atoms, as illustrated by, but not limited to,cyclopropyl, cyclobutyl, 2-methylcyclobutyl and cyclohexyl.

As used herein the terms "lower-alkenyl" and "lower-alkynyl" meanmonovalent, aliphatic radicals of from three to six carbon atoms whichcontain at least one double or triple bond, and are either straight orbranched-chain as illustrated by, but not limited to, 1-(2-propenyl),1-(1-propenyl), 1-(3-methyl-2-propenyl), 1-(1,3-dimethyl-2-propenyl),1-(2-hexenyl), 1-(2-propynyl) and 1-(2-butynyl).

As used herein, the term "lower-alkylene" means divalent, aliphaticradicals, including straight or branched-chain radicals, of from two toeight carbon atoms, and having its valences on different carbon atoms asillustrated by, but not limited to, 1,2-ethylene, 1,4-butylene,1,6-hexylene, 3-methyl-1,5-pentylene and 1,8-octylene.

The compounds of Formula I where X is O; R₁ and R₂ are each hydrogen;and R₃, R₄, R₅, R₆ and R₇ have the meanings given above are prepared byhydrolysis, under acid, basic or neutral conditions, of thecorresponding 2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrileshaving the Formula II: ##STR6## where R₃, R₄, R₅ and R₆ have themeanings given above, and R₇, in addition to the various meanings givenabove, represents cyano-lower-alkyl. Hydrolysis under basic conditionsis advantageously effected by warming a solution of the nitrile ofFormula II in an inert organic solvent, for example methanol, ethanol orisopropanol, containing a molar excess of an alkali metal hydroxide.Hydrolysis in a neutral medium is advantageously carried out using theprocedure of Bennett et al., J. Am. Chem. Soc. 95, 3030-1 (1973) inwhich a planar, nonionic tertiary phosphine metal-hydroxy complex isused as a catalyst. Hydrolysis in an acid medium is carried out byheating a solution of the nitrile in a mineral acid, for example,phosphoric acid, polyphosphoric acid or aqueous sulfuric acid at atemperature from 0° C. to around 70° C. During the reaction, the nitrilegroup in the compounds of Formula II where R₇ is cyano-lower-alkyl ishydrolyzed simultaneously with the nitrile group attached to the4-position of the 2,4,5,6-tetrahydrocyclopenta[c]pyrrole to thus producecompounds of Formula I where R₇ is carboxamido-lower-alkyl, and theabove-described procedure constitutes a preferred method of preparingthe latter compounds.

The compounds of Formula I where X is S; R₁ and R₂ are each hydrogen;and R₃, R₄, R₅, R₆ and R₇ have the meanings given above are preferablyprepared by thiohydrolysis of the nitriles of Formula II using theprocedure of Karrer et al., Helv. Chim. Acta 28, 820 (1945) whichinvolves reacting the nitrile with a saturated solution of ammonia andhydrogen sulfide in an organic solvent, preferably a lower-alkanol, atroom temperature. Alternatively, the reaction can be carried out underpressure in an autoclave at a temperature from 150°- 160° C. using theprocedure described by Ralston et. al., J. Org. Chem. 4, 68 (1939). Asin the case of the hydrolysis of the compounds of Formula II to those ofFormula I where X is O, thiohydrolysis of the compounds of Formula IIwhere R₇ is cyano-lower-alkyl affords the compounds of Formula I whereR₇ is thiocarboxamido-lower-alkyl, and the above-described procedureconstitutes a preferred method of preparing the latter compounds.

Alternatively, and preferably, the compounds of Formula I where X is Sare prepared by reaction of the corresponding compounds where X is Owith phosphorus pentasulfide. The reaction is carried out by heating thereactants directly either with or without a solvent. Preferred solvents,when used, are benzene, toluene, xylene, dioxane and the like.

The compounds of Formula I where R₇ is other than hydrogen can also beprepared by reaction of the corresponding compounds where R₇ is hydrogenwith a strong base, for example alkali metal hydrides or alkali metalamides, in an inert organic solvent, for example dimethylsulfoxide,dioxane, dimethylformamide, tetrahydrofuran, dibutyl ether, and thelike, and reaction of the resulting salt with an appropriate alkylatingagent, R₇ X, where X is the anion of a strong mineral acid, for examplea hydrogen halide or sulfuric acid, and R₇ has the meanings given above.The reaction is preferably carried out at low temperatures, i.e. from 0°C. to about 40° C. During the reaction, alkylation can take place ateither the amide nitrogen atom, when compounds where R₁ and R₂ are bothhydrogen are used as starting materials, or at the pyrrole nitrogenatom, and it is possible to isolate both isomeric products from thereaction mixture.

The compounds of Formula I where R₇ is lower-alkenyl are preferablyprepared by Hofmann elimination of a tertiary amine from a compound ofFormula I where R₇ is di-lower-alkylamino-lower-alkyl,morpholino-lower-alkyl, 1-pyrrolidyl-lower-alkyl or1-piperidyl-lower-alkyl. The method comprises converting the tertiaryamine to a quaternary ammonium salt by reaction of the amine with anester of a strong inorganic acid, e.g. a lower-alkyl halide or adi-lower-alkyl sulfate, and reacting the quaternary salt with silveroxide, preferably in an aqueous medium to effect conversion of thequaternary salt to the corresponding ammonium hydroxide, whichspontaneously decomposes in an aqueous medium at ambient temperature tothe N-lower-alkenyl-substituted compound of Formula I and a tertiaryamine. It is preferred to use a dimethylamino-lower-alkyl-substitutedcompound of Formula I as starting material and a methyl halide ordimethyl sulfate as quaternizing agent.

The compounds of Formula I where R₁ and/or R₂ are other than hydrogenand R₇ is other than hydrogen are prepared by reacting the correspondingcarboxamides where either one or both of R₁ and R₂ are hydrogen with astrong base, for example an alkali metal hydride or an alkali metalamide, followed by reaction of the resulting salt with an alkylatingagent, for example a lower-alkyl halide or a di-lower-alkyl sulfate. Asindicated above, when compounds where both R₁ and R₂ are hydrogen areused as starting materials, alkylation can take place on both the ringand amide nitrogen atoms, necessitating separation of the isomericproducts. Preparation of the compounds where both R₁ and R₂ arelower-alkyl is best effected by stepwise alkylation of the carboxamide,that is alkylation of the compounds where both R₁ and R₂ are hydrogenusing one mole of a strong base and one mole of an alkylating agentfollowed by a second alkylation of the resultingN-lower-alkylcarboxamide where one of R₁ and R₂ is lower-alkyl. Thereaction with a second mole of strong base takes place under much morevigorous conditions involving use of higher reaction temperatures, i.e.from about 50° C. to about 150° C., and longer reaction times than theabove-described method for alkylation at the pyrrole nitrogen atom ormonoalkylation at the amide nitrogen atom, which take place at lowertemperatures and shorter reaction times. The reaction is carried out inan inert organic solvent, for example dimethylsulfoxide, dioxane,dimethylformamide, tetrahydrofuran, dibutyl ether, and the like.

The compounds of Formula I where one or both R₆ groups are hydroxymethyl(R₈, R₉ and R₁₀ are hydrogen), are prepared by reduction, with an alkalimetal borohydride, of the corresponding compounds of Formula I where oneor both R₆ groups are formyl. The reaction is carried out in an inertorganic solvent, for example lower-alkanols, dioxane, diethyl ether, andthe like. The reaction generally takes place at ambient temperature,although elevated temperatures up to the boiling point of the solventcan be used to expedite the reaction. The method for the preparation ofcompounds where both R₆ groups are hydroxymethyl is represented by theequation: ##STR7## where R₁, R₂, R₃, R₄, R₅, R₇, and X have the meaningsgiven above.

The compounds of Formula I where one or both R₆ moieties is the group##STR8## where R₈ is hydrogen and R₉ is lower-alkyl, lower-alkynyl,lower-alkenyl, phenyl, phenyl-lower-alkyl or trichloromethyl areprepared by reaction of the corresponding compound where one or both R₆groups is formyl with an organo metallic compound such as an organolithium, e.g. a lower-alkyl, lower-alkenyl, lower-alkynyl or phenyllithium, or an organo magnesium halide, e.g. phenyl (orsubstituted-phenyl) magnesium halide or a phenyl-lower-alkyl magnesiumhalide, and hydrolysis of the resulting organometallic compound. Thereaction is carried out in an inert organic solvent such astetrahydrofuran or diethyl ether.

The compounds of Formula I where R₈ is lower-alkyl, lower-alkynyl,lower-alkenyl, phenyl or phenyl-lower-alkyl and R₉ is the same ordifferent lower-alkyl, lower-alkynyl, lower-alkenyl, phenyl orphenyl-lower-alkyl are prepared by reacting the corresponding compoundswhere R₆ is carbo-lower-alkoxy with either four molar equivalents of anorgano metallic compond as indicated above, which affords compoundswhere R₈ and R₉ are identical, or if desired only two moles of theorgano metallic compound can be used which affords compounds where R₆ isa ketone group, i.e. R₈ -CO (or R₉ -CO). The latter is then reacted withtwo moles of a different organo metallic compound to give the carbinolswhere R₈ and R₉ are different. In each of the above-described reactionsrequiring use of an organo metallic compound, one mole of the organometallic reagent in addition to that required for reaction at the 1- or3-positions is required when the compounds of Formula I where one orboth of R₁ and R₂ is hydrogen is used as the starting material, becauseone mole of the organo metallic reagent reacts with one of the protonson the amide nitrogen.

The compounds of Formula I where R₉ is cyano, carbamyl or aminomethylare prepared via the cyanohydrin (i.e. R₉ is cyano) of the correspondingcompounds where R₆ is formyl. The cyanohydrins are prepared by reactionof the formyl compounds with diethyl aluminum cyanide in an inertorganic solvent, for example benzene, toluene, xylene, tetrahydrofuran,dioxane or mixtures of these solvents. A preferred solvent is a mixtureof benzene and tetrahydrofuran. The cyanohydrins in turn, on eitherhydrolysis with dilute sulfuric acid using the same conditions asdescribed for hydrolysis of the compounds of Formula II to Formula I, orcatalytic reduction with hydrogen over platinum oxide afford,respectively, the compounds where R₉ is carbamyl and aminomethyl.

The compounds of Formula I where R₉ is carboxy or carbo-lower-alkoxy areprepared by hydrolysis of the corresponding compounds where R₉ istrichloromethyl, using the procedure described below for preparing thecompounds where R₆ is formyl or carboxy, to afford the compounds whereR₉ is carboxy. The esters are prepared from the acids by standardesterification procedures.

The compounds of Formula I where R₉ is lower-alkanoyl are prepared byhydroxylation of the corresponding compounds where R₉ is lower-alkynylusing dilute sulfuric acid.

The compounds of Formula I where R₁₀ is lower-alkyl are prepared byreacting the free carbinols (R₁₀ is hydrogen) with a lower-alkanol inthe presence of a mineral acid. The compounds where R₁₀ is an estergroup, i.e. benzoyl, lower-alkanoyl or carboxy-lower-alkanoyl areprepared by reacting the carbinol either with an acid halide or an acidanhydride in the presence of an acid acceptor, for example pyridine or atri-lower-alkylamine.

The intermediate,2,4,5,6-tetrahydrocyclopenta[c]-pyrrole-4-carbonitriles of Formula IIare prepared by a variety of different methods depending upon theidentities of the various R₃, R₄, R₅, R₆ and R₇ groups. For example, thenitriles where R₃, R₄ and R₅ are each methyl, one or both R₆ groups arelower-alkyl or phenyl-lower-alkyl, and R₇ is hydrogen, which arerepresented by Formula IIa, are prepared by reaction of an alkanedione(or diphenylalkanedione), in which the two keto groups are separated bytwo carbon atoms as represented by Formula III, with2-amino-2-methylpropionitrile having the Formula IV. The method isrepresented by the reaction: ##STR9## where R₆ has the meanings givenabove, and takes place in an acid medium, preferably a lower-alkanoicacid, particularly glacial acetic acid. Surprisingly, the reaction doesnot produce a pyrrole derivative having an α,α-dimethylacetonitrilegroup attached to the nitrogen atom of the pyrrole ring, as might beexpected, but instead affords the 2,4,5,6-tetrahydrocyclopenta[c]pyrrolederivatives of Formula IIa above-indicated. The reaction is preferablycarried out in the presence of a stoichiometric amount of a strongeracid, for example, trifluoroacetic acid (preferred), trichloroaceticacid or phosphoric acid.

Alternatively, the same transformation can be effected by use of excessacetone and a source of ammonia, e.g. an ammonium salt such as ammoniumacetate, and a source of cyanide ion, e.g. an alkali metal cyanide, inplace of the 2-amino-2-methylpropionitrile. The reaction is carried outunder the same conditions described above for the reaction based on2-amino-2-methylpropionitrile.

Alternatively, the compounds of Formula II where R₃, R₄ and R₅ are eachmethyl, one or both R₆ groups are lower-alkyl or phenyl-lower-alkyl, andR₇ has the various meanings given above, which are represented byFormula IIb below, can be prepared by reaction of2-amino-2-methylpropionitrile having the Formula IV above oracetonecyanohydrin having the formula: ##STR10## with a 1-R₇ -2,5-di-R₆-substituted-pyrrole having the Formula V using the same reactionconditions as described above for the preparation of the compounds ofFormula IIa using the alkanedione route. In addition, the presence of astrong organic acid such as chloroacetic acid or trifluoroacetic acid isdesirable. The method is represented by the reaction: ##STR11## where R₆and R₇ have the meanings given above.

Alternatively, the same transformation can be effected by use of excessacetone, along with a source of ammonia, e.g. an ammonium salt such asammonium acetate, and a source of cyanide ion, e.g. an alkali metalcyanide, in place of the 2-amino-2-methylpropionitrile. The reaction iscarried out under the same conditions described above for the reactionbased on 2-amino-2-methylpropionitrile.

The 1-R₇ -2,6-di-R₆ -substituted-pyrroles of Formula V where one or bothR₆ groups are lower-alkyl or phenyl-lower-alkyl are in turn prepared byreacting an alkanedione or diphenylalkanedione having the Formula IIIabove with an appropriate amine, R₇ NH₂, under dehydrating conditions.The reaction is preferably carried out by refluxing the reactants in awater-immiscible organic solvent, for example benzene, toluene orxylene, using a water separator, i.e. a Dean-Stark trap, to separate thewater and remove it from the reaction medium as it is formed during thereaction.

Alternatively, the compounds of Formula II where R₃, R₄ and R₅ aremethyl, one or both R₆ groups are lower-alkyl or phenyl-lower-alkyl, andR₇ has the various meanings given above, which are represented byFormula IIb, are prepared by condensation of a 1-R₇ -2,5-di-R₆-substituted-pyrrole of Formula V with excess acetone in the presence ofa source of cyanide ion, e.g. an alkali metal cyanide, and a molarexcess of a mineral acid, for example hydrochloric acid or sulfuricacid. The resulting 3,3,3',3'-tetramethyl-4,4',6,6'-tetra-R₆-1,1'-spirobis(cyclopenta[4,5-c]pyrrole) of Formula VI is then reactedwith a source of ammonia, e.g. ammonium acetate, and a source of cyanideions, e.g. an alkali metal cyanide, in the presence of glacial aceticacid. The initial condensation of the 1-R₇ -2,5-di-R₆-substituted-pyrrole of Formula V with acetone preferably takes place byshort refluxing of the reactants. The method is represented by thefollowing reactions: ##STR12## where R₆ and R₇ have the meanings givenabove. Alternatively, the compounds of Formula IIb are prepared byreaction of one mole of a compound of Formula IV with one mole ofacetone.

Alternatively, the 3,3,3',3'-tetramethyl-4,4' ,6,6'-tetra-R₆-1,1'-spirobis(cyclopenta[4,5-c]pyrroles) of Formula VI can be preparedby reaction of a 1-R₇ -2,5-di-R₆ -substituted-pyrrole of Formula V witha molar excess of 2-amino-2-methyl propionitrile of Formula IV,preferably in the presence of a strong organic acid using the sameconditions as described above for the preparation of the compounds ofFormula IIb from a 1-R₇ -2,5-di-R₆ -substituted-pyrrole of Formula V and2-amino-2-methylpropionitrile of Formula IV. In fact, the spirocompounds can often be isolated as a by-product in the latter process.

The compounds of Formula II where both R₆ groups are formyl are preparedby reaction of the compounds of Formula IIc, where both R₆ groups aremethyl and R₃, R₄, R₅, and R₇ have the meanings given above, with fourmoles of sulfuryl chloride, which affords the corresponding compoundswhere each R₆ group is dichloromethyl (Cl₂ CH), represented by FormulaIId, followed by hydrolysis of the latter with water and a watermiscible organic solvent, which only serves to promote solution of thestarting material, for example dioxane, acetone, ethylene glycol, or alower-alkanol, to give the corresponding compounds where both R₆ groupsare formyl, where are represented by Formula IIe. The method isrepresented by the following reactions: ##STR13## where R₃, R₄, R₅, andR₇ have the meanings given above.

The 1,3-diformyl compounds of Formula IIe are particularly valuableintermediates for the preparation of the final products of Formula I inwhich the two R₆ moieties are different, because one of the two formylgroups can be individually protected while other transformations arecarried out on the other formyl group after which the protecting groupcan be removed to regenerate the formyl group which can then either bepreserved in the final products or if desired utilized as a handle forconversion to other groups such as various carbinols as described above.A particularly effective means of protecting one of two formyl groups isto convert the latter to a ketal by reaction of the formyl derivativewith one molar equivalent of an alkanediol (or with two molarequivalents of a lower-alkanol) in an anhydrous medium and in thepresence of a strong acid. Preferred alkanediols are 1,3-propanediolswhich may be straight or branched, for example, 2,2-dimethyl-propanediolor 1,1,3-trimethyl-1,3-propanediol (i.e. 2-methyl-pentane-2,4-diol). Theresulting mixture of products containing a ketal group at each of the 1-and 3-positions can, if desired, be separated into the individualcomponents, and each component treated separately in subsequentsynthetic steps. The unprotected formyl group can then, for example, beoxidized to the carboxylic acid using an alkaline medium in which theketal group is stable, for example alkaline permanganate. The carboxylgroup thus produced can either be retained as such or converted to anester moiety or, if desired, it can be removed by heating the product ata temperature of around 200°-250° C. in a high boiling organic solvent,for example dimethylaniline, ethylene glycol or propylene glycol.

The compounds of Formula I and II where one or both R₆ groups arecarboxy are prepared by oxidizing the corresponding compounds where oneor both R₆ groups are formyl with one mole of an oxidizing agent performyl group, for example alkaline permanganate as described above. Thecorresponding compounds of Formulas I and II where one R₆ group isformyl and the other a carboxy group can also be prepared by reaction ofthe corresponding compound of Formula I or II where both R₆ groups aremethyl with five molar equivalents of sulfuryl chloride, which affordsthe compounds where one R₆ group is dichloromethyl and the othertrichloromethyl, and hydrolysis of the latter with water in awater-miscible organic solvent as described above. The compounds whereone or both R₆ groups are carbo-lower-alkoxy are prepared from compoundswherein one or both R₆ groups are carboxy by standard esterificationprocedures comprising reacting the carboxylic acid with a lower-alkanol.

The compounds of Formula II where one or both R₆ groups are hydrogen,which are presented by Formula IIf, are prepared by decarbonylation ofthe corresponding compounds where one or both R₆ groups are formyl,which are represented by Formula IIe above, over a palladium-on-charcoalcatalyst. The reaction is carried out in an inert organic solvent,preferred solvents being glycols having a boiling point around 200° C.or higher, for example ethylene glycol, propylene glycol, glycerol, andthe like. The reaction is preferably carried out at an elevatedtemperature, i.e. at the boiling point of the solvent used, which servesto shorten the reaction time but is otherwise not critical. The reactionis represented by the equation: ##STR14## where R₃, R₄, R₅ and R₇ havethe meanings given above. For the sake of brevity, the reaction is shownas involving the decarbonylation of formyl groups at both the 1- and3-positions, but it is to be understood that the method can be used toeffect decarbonylation of compounds having formyl groups at either oneor both of the 1- and 3-positions of the compounds of Formula II.Moreover, although the method is shown as being applied only to thecompounds of Formula II, decarbonylation at either or both of the 1- and3-positions can also be carried out on the final products of Formula I.

The compounds of Formula II where R₃ is lower-alkyl; R₄ and R₅ arehydrogen; one or both R₆ groups are lower-alkyl or phenyl-lower-alkyl;and R₇ has the various meanings given above, which are represented byFormula IIg below, are prepared by a sequence of reactions involving,first, conversion of a 1-R₇ -2,5-di-R₆ -substituted-pyrrole of Formula Vto the corresponding 3-formyl derivative having the Formula VIII by theVilsmeier-Haack reaction, which comprises reacting the pyrrole withdimethylformamide in the presence of phosphorus oxychloride at atemperature in the range from 50°-100° C. and decomposition of themixture with aqueous sodium acetate; conversion of the formyl compoundto the corresponding 3-acrylonitrile derivative of Formula IX byreaction of the formyl derivative with sodium hydride indimethylformamide, followed by reaction of the resulting sodium saltwith diethoxyphosphonoacetonitrile ##STR15## in ethylene glycol dimethylether; catalytic reduction of the resulting acrylonitrile derivative tothe corresponding propionitrile derivative of Formula X; hydrolysis ofthe latter with methanolic potassium hydroxide to the correspondingpropionic acid; cyclization of the latter by heating with polyphosphoricacid; and reaction of the resulting 4-oxo-2,4,5,6-tetrahydro-1,3-di-R₆-2-R₇ -cyclopenta[c]pyrrole of Formula XI with a lower-alkyl magnesiumhalide followed by heating the resulting carbinol with a molar excess ofa 1:1 mixture of potassium cyanide and potassium acetate in glacialacetic acid. The method is represented by the following reactions:##STR16## where R₃, R₆ and R₇ have the meanings given above.

This same general approach can be utilized to prepare the compounds ofFormula II where R₃ and R₄ are either hydrogen or the same or differentlower-alkyl. Thus, reaction of a 1-R₇ -2,5-di-R₆ -pyrrole with eitherdimethylformamide (R₄ is hydrogen) or a dimethyl-lower-alkanamide (R₄ islower-alkyl) in the presence of phosphorus oxychloride; reaction of theresulting 1-R₇ -2,5-di-R₆ -4-R₄ CO-pyrrole with ethyldiethoxy-phosphonoacetate in ethylene glycol dimethyl ether; catalyticreduction of the resulting ethyl acrylate derivative to thecorresponding ethyl propionate; hydrolysis of the latter to thecorresponding propionic acid; cyclization of the latter by heating withpolyphosphoric acid; and either reaction of the resulting4-oxo-2,4,5,6-tetrahydro-1,3-di-R₆ -2-R₇ -cyclopenta[c]pyrrole with alower-alkyl magnesium halide (R₃ is lower alkyl) or by reduction of theformer with sodium borohydride, followed in either case by heating theresulting carbinol with a molar excess of a 1:1 mixture of potassiumcyanide and potassium acetate in glacial acetic acid. The method isrepresented by the following reaction sequence: ##STR17## where R₃, R₄,R₆ and R₇ have the meanings given above.

The compounds of Formula II where R₃ is methyl and R₄ and R₅ are eitherhydrogen or lower-alkyl can also be prepared by reaction of a 1-R₇-2,5-di-R₆ -4-R₄ CO-pyrrole of formulas VIII (R₄ is hydrogen) or VIIIa(R₄ is lower-alkyl) with a lower-alkyl magnesium halide (R₅ islower-alkyl) or reduction of the ketone to the carbinol with sodiumborohydride (R₄ and R₅ are both hydrogen) and reaction of the resultingcarbinol with one molar equivalent of acetone and two molar equivalentseach of potassium cyanide and potassium acetate in glacial acetic acid.The latter reaction is carried out at the reflux temperature of thereaction mixture. The method is represented by the following reactionsequence: ##STR18## where R₄, R₅, R₆ and R₇ have the meanings givenabove.

The compounds of Formula II where R₃, R₄ and R₅ have all the variousmeanings given above, one or both R₆ groups are hydrogen, lower-alkyl orphenyl-lower-alkyl, and R₇ is lower-alkyl,di-lower-alkylamino-lower-alkyl, morpholino-lower-alkyl,1-pyrrolidyl-lower-alkyl, 1-piperidyl-lower-alkyl,cycloalkyl-lower-alkyl, phenyl-lower-alkyl, cyano-lower-alkyl,carbo-lower-alkoxy-lower-alkyl, carboxamido-lower-alkyl ordivalent-lower-alkylene can also be prepared by reacting thecorresponding compounds where R₇ is hydrogen with a strong base, forexample an alkali metal hydride or an alkali metal amide, in an inertorganic solvent, for example dimethylsulfoxide, dioxane,dimethylformamide, tetrahydrofuran or dibutyl ether, and reacting theresulting salt with an appropriate alkylating agent, R₇ X, where X isthe anion of a strong mineral acid, for example a hydrogen halide orsulfuric acid, and R₇ has the meanings given above. The reaction takesplace at a temperature in the range from 15° C. to about 70° C. and ispreferably carried out in dimethyl sulfoxide. The same compounds whereR₇ is 2-cyanoethyl, 2-(carbo-lower-alkoxy)-ethyl or 2-carboxamidoethylare prepared by reaction of the compounds of Formula II where R₇ ishydrogen with acrylonitrile, an acrylic ester or acrylamide,respectively, in the presence of a strong base, for examplebenzyltrimethylammonium hydroxide. The reaction is carried out in aninert organic solvent, for example dioxane, diethyl ether,tetrahydrofuran, and the like. The reaction generally takes place atroom temperature.

The compounds of formula I where R₁ and R₂ are each hydrogen can also beprepared by reduction with one molar equivalent of diisobutyl aluminumhydride (DIBAL), of the compounds of Formula II, and oxidation withoxygen of the resulting cyclopenta[c]pyrrole-4-aldimide having theFormula XX without isolation of the latter. The method is illustrated bythe following reaction sequence; ##STR19##

The compounds of Formula XX can also be converted to the final productsof Formula I where R₁ and R₂ are hydrogen and X is O by reacting thealdimide of Formula XX with a peracid, e.g. performic, peracetic orperbenzoic acid, to produce an oxaziridine having the Formula XXI, whichon thermal or photochemical decomposition by irradiation with lightaffords the compounds of Formula I. The method is represented by thereaction sequence: ##STR20## where R₃, R₄, R₅, R₆ and R₇ have themeanings given above.

Still another method for converting the carbonitriles of Formula II tothe carboxamides of Formula I where R₁ and R₂ are hydrogen and X is Ocomprises oxidizing the carbonitrile with peroxide, e.g. hydrogenperoxide, in a basic medium, e.g. in the presence of an alkali metalhydroxide, and decomposition of the resulting perimidate of Formula XXIIby heating the reaction medium. A preferred solvent is acetone. Themethod is represented by the reaction sequence: ##STR21## where R₃, R₄,R₅, R₆ and R₇ have the meanings given above.

The compounds of Formula II, wherein R₃, R₄ and R₅ are each methyl, andeach R₆ group is the same or different hydrogen, phenyl-lower-alkyl orlower-alkyl, can also be prepared by reaction of a5,6-dihydro-1H-furo[3,4-c] pyrrole having the Formula XXIII with cyanidein glacial acetic acid with or without added trifluoroacetic acid. Thecompounds of Formula XXIII are in turn prepared by reaction of a1,2-di-R₆ CO-1,2-diacetylethane of Formula XIV with an amine, R₇ NH₂,and reaction of the resulting 2,5-di-R₆ -3,4-diacetylpyrrole of FormulaXXIV with a methyl magnesium halide. The latter reaction affords thecompounds of Formula XXIII directly. The overall method is illustratedby the following reaction sequence where R₆ and R₇ have the meaningsgiven above. ##STR22##

With the exception of the compounds of Formula V, whose method ofpreparation has been described, all the other starting materials hereinare well-known groups of compounds, and many are commercially available.

The novel compounds of the instant invention are the compounds ofFormulas I and II and the acid-addition salts of the former in which R₇is a basic, salt-forming group such as di-lower-alkylamino-lower-alkyl,morpholino-lower-alkyl, 1-pyrrolidyl-lower-alkyl,1-piperidyl-lower-alkyl or a basic heterocyclic group such as pyridyl.The compounds of Formula I in free base form are converted to theacid-addition salt form by interaction of the base with an acid in anorganic solvent and isolating the salt directly or by concentration ofthe solution. In like manner, the free base can be regenerated from theacid-addition salt form in the conventional manner, that is by treatingthe salts with cold, week aqueous bases, for example alkali metalcarbonates and alkali metal bicarbonates. The bases thus regenerated canthen be interacted with the same or a different acid to give back thesame or a different acid-addition salt. Thus the original bases and allof their acid-addition salts are readily interconvertible.

In standard biological test procedures, described generally by Shay etal., Gastroenterology 5, 43 (1945) and 26, 906 (1954), the compounds ofFormula I have been found to possess anti-secretory and anti-ulceractivity and are thus useful as anti-secretory and anti-ulcer agents.Anti-secretory activity was determined in male albino Wistar ratsweighing approximately 180 g. using the test procedure described asfollows: the rats were divided into medicated groups of at least fiverats each and control groups of 10 rats. The rats were medicated orallyonce daily for two days prior to stomach ligation and once againimmediately following ligation. All drugs were administered as the freebase, and control rats received only the vehicle of medication. The ratswere housed individually in wire cages, and food was withdrawn 48 hoursprior to surgery, and water was withdrawn at the time of surgery.Laparotomy was performed under light ether anesthesia, thepyloric-duodenal junction was ligated, and the wound was closed withmetal clips and sprayed with a protective surgical dressing. Five hoursfollowing surgery, the rats were sacrificed, the stomach was removed,and the gastric juice collected. The gastric fluid was centrifuged, andtotal volume, color, and volume of solids were recorded. The pH of thegastric fluid was then determined on a Beckman pH meter, and the "free"and "total" acid was determined from an aliquot of the gastric fluid bytitrating with 0.1N sodium hydroxide against Toepfers reagent andphenolphthalein, respectively. The difference between the average amountof "free" acid (expressed as milliequivalents of hydrochloric acid perliter of gastric fluid) of the medicated and control groups wasexpressed as per cent gastric secretory change.

The anti-ulcer activity of the compounds was determined using thereserpine-induced anti-ulcer test method which is described briefly asfollows: male, albino, Sprague-Dawley rats, weighing approximately 300g., were divided into medicated and control groups of at least five ratseach, and one positive control group of five rats medicated with a knowndrug at the active dose was run with each experiment. The rats weremedicated 48, 24, and 1 hour before receiving an injection of reserpine.All test drugs were administered orally in terms of base, and thecontrol rats received only the vehicle of medication. The rats werehoused individually in wire cages, and food was withdrawn twenty-fourhours prior to injection of reserpine, while water was allowed adlibitum. One hour following the third medication, 5.0 mg. of reserpineper kilogram of body weight in a concentration of 5 mg./ml. was injectedintramuscularly in each rat. Eighteen hours after injection the ratswere sacrificed, their stomachs removed, opened along the greatercurvature, rinsed in warm saline, and pinned to a cork board for grossobservation. The stomachs were examined for the number and size ofulcerations located in the glandular portion of the stomach with the aidof a 1 millimeter grid ocular with a 10x dissecting microscope. Thedegree of ulceration was arbitrarily graded according to the number andsize of the ulcers as follows:

0 <1 mm.² 1 point

1 <3 mm.² 2 points

≧3 mm.² 5 points.

The points were added together and divided by the number of rats in eachgroup to give an ulcer score, and the difference in the mean scores ofthe medicated and control group was expressed as per cent inhibition ofulceration.

The compounds of Formula I were thus found to inhibit secretion ofgastric fluids and to inhibit reserpine-induced stomach ulceration whenadministered in a dose range of from around 10 mg./kg. to around 200mg./kg. The compounds are preferably administered orally, and the amountof a particular compound to be administered, either alone or as theessential active ingredient in a formulation, will range from about 10to about 200 mg./kg.

The actual determination of the numerical biological data definitive fora particular compound of Formula I is readily determined by standardtest procedures by technicians versed in pharmacological test procedureswithout the need for an extensive experimentation.

The compounds of Formula I can be prepared for use by incorporation inunit dosage form as tablets or capsules for oral administration eitheralone or in combination with suitable adjuvants such as calciumcarbonate, starch, lactose, sodium bicarbonate, sodium lauryl sulfate,sugar, dextrose, mannitol, cellulose, gum acacia, and the like.Alternatively, they can be formulated for oral administration in aqueousalcohol, glycol, or oil solutions or oil-water emulsions in the samemanner as conventional medicinal substances are prepared. They can alsobe formulated for oral use with foodstuffs or admixed with foodstuffsfor veterinary use.

The molecular structures of the compounds of the invention were assignedon the basis of study of their infrared, ultraviolet, and NMR spectra,and confirmed by the correspondence between calculated and found valuesfor elementary analyses for the elements.

The following examples will further illustrate the invention without,however, limiting it thereto. All melting points are uncorrected.

I. INTERMEDIATES A. INTERMEDIATES OF FORMULA V: EXAMPLE 1

A mixture of 57 g. (0.5 mole) of 2,5-hexanedione and 43.5 g. (0.56 mole)of 40% aqueous methylamine in 250 ml. of benzene was refluxed under aDean-Stark trap until no more water was carried over, and the resultingsolution was taken to dryness. The residual oily material was distilledin vacuo to give 34 g. of 1,2,5-trimethylpyrrole, b.p. 58°-59° C./20 mm.

Following a procedure similar to that described in Example 1, using anappropriate alkanedione of Formula III and an appropriate amine, R₇ NH₂,the following 1-R₂ -2,5-di-R₆ -substituted-pyrroles of Formula V wereprepared. Here and elsewhere throughout this specification in subsequenttables, the weights of the starting materials and products are given ingrams in the appropriate columns headed "Wt. ", and melting points orboiling points of the final products, together with the solvent ofrecrystallization (for solids) or pressure in mm. of mercury (at theboiling point for liquids) as the case may be, are given in the lastcolumn. Where weights of only one of several reactants are given, theweights of such other reactants can be calculated on a proportionatemolar basis from the amounts used in the example referred to for thepreparative procedure employed. Moreover, in each of the tables whichfollow, both R₆ groups in each of the products are identical unlessspecifically noted otherwise. Where the R₆ groups are different, thesubstituents represented by the R₆ moieties are designated (1) and ( 3)to indicate location of the substituents at the 1- and 3-positions,respectively, of the cyclopenta[c]pyrrole nucleus.

In some instances, the products were neither characterized nor purified,either by distillation or recrystallization, but rather were useddirectly in the next step as isolated from the reaction mixture.

                                      Table 1a                                    __________________________________________________________________________                                       m.p. (° C.)/Solvent or              Example                                                                             R.sub.6                                                                           R.sub.7        Wt.III                                                                             Wt. V                                                                              b.p. (° C.)/mm.Hg.                  __________________________________________________________________________    1A    CH.sub.3                                                                          (CH.sub.2).sub.6                                                                             114  66   102-105/cyclohexane                        1B    CH.sub.3                                                                          CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                            57   91   163-165/15-20                              1C    CH.sub.3                                                                          4-NH.sub.2 SO.sub.2 C.sub.6 H.sub.4                                                          114  118  157-158.5/methanol                         1D    CH.sub.3                                                                          C.sub.6 H.sub.5                                                                              114  152  155-160/15                                 1E    CH.sub.3                                                                          C.sub.2 H.sub.5                                                                              57   95   75-78/15-20                                1F    CH.sub.3                                                                          C.sub.3 H.sub.7                                                                              114  103  80-82/15-20                                1G    CH.sub.3                                                                          4-CH.sub.3 OC.sub.6 H.sub.4                                                                  114  162  104-105/0.01                               1H    CH.sub.3                                                                          4-CH.sub.3 C.sub.6 H.sub.4                                                                   114  143  65-76/0.05                                 1J    CH.sub.3                                                                          4-ClC.sub.6 H.sub.4                                                                          114  169  104/0.04                                   1K    CH.sub.3                                                                          3-ClC.sub.6 H.sub.4                                                                          114  188  96-98/0.05                                 1L    CH.sub.3                                                                          2-pyridyl      114  132  74-90/0.03                                 1M    CH.sub.3                                                                          3-CH.sub.3 C.sub.6 H.sub.4                                                                   114  158  78-80/0.05                                 1N    CH.sub.3                                                                          2-ClC.sub.6 H.sub.4                                                                          114  174  84-94/0.05                                 1P    CH.sub.3                                                                          2-CH.sub.3 C.sub.6 H.sub.4                                                                   114  143  117-119/0.05                               1Q    CH.sub.3                                                                          4-FC.sub.6 H.sub.4                                                                           114  155  116-120/15                                 1R    CH.sub.3                                                                          4-(CH.sub.3).sub.2 NC.sub.6 H.sub.4                                                          57   79   methanol                                   1S    CH.sub.3                                                                          4-HOC.sub.6 H.sub.4                                                                          114  161  121-138/0.05-0.5                                                              m.p. 102-105                               1T    CH.sub.3                                                                          4-CH.sub.3 CONHC.sub.6 H.sub.4                                                               114  169  methanol                                   1U    CH.sub.3                                                                          iso-C.sub.3 H.sub.7                                                                          57   49.7 80-82.5/17                                 1V    CH.sub.3                                                                          CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                           62.7 67.1 105-108.5/760                                                                 n.sub.D.sup.26 1.4845                      1W    CH.sub.3                                                                          CH.sub.2 COOC.sub.2 H.sub.5                                                                  62.7 73.9 125-127/13                                                                    n.sub.D.sup.23 1.4903                      1X    CH.sub.3                                                                          cyclohexyl     114  132  83-89/0.02                                 1Y    C.sub.2 H.sub.5                                                                   C.sub.6 H.sub.5                                                                              7.6  12.3 Dark oil                                   1Z    CH.sub.3                                                                          cyclopropyl    50   52.8 36-39/0.3                                  1AA   CH.sub.3                                                                          cyclopentyl    57.1 66.7 63-72/0.03                                                                    n.sub.D.sup.25 1.5210                      1AB   CH.sub.3                                                                          CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                          46.3 58.5 48/0.03                                                                       n.sub.D.sup.25 1.4922                      1AC   CH.sub.3                                                                          CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O                                               22.8 37.6 89-104/0.05                                                                   n.sub.D.sup.25 1.5167                      1AD   CH.sub.3                                                                          CH.sub.2 CH.sub.2 CH.sub.2 OH                                                                34.2 38.5 83-96/0.05                                 1AE   CH.sub.3                                                                          cyclobutyl     21.2 18.2 50-55/0.2                                                                     n.sub.D.sup.25 1.5202                      1AF   CH.sub.3                                                                          4-HOOCC.sub.6 H.sub.4                                                                        114  106  m.p. 202-204                               1AG   CH.sub.3                                                                          4-O.sub.2 NC.sub.6 H.sub.4                                                                   114  103  m.p. 146-149                               1AH   CH.sub.3                                                                          sec.-C.sub.4 H.sub.9                                                                         55.6 55.7 90-94/21                                   1AJ   CH.sub.3                                                                          iso-C.sub.4 H.sub.9                                                                          68.4 82.4 94-95/22                                   1AK   CH.sub.3                                                                           ##STR23##     5.7  10.4 m.p. 100-111                               1AL   CH.sub.3                                                                          4-C.sub.2 H.sub.5 OC.sub.6 H.sub.4                                                           34.2 51.2 101-107/0.4                                1AM   CH.sub.3                                                                          3-CF.sub.3 C.sub.6 H.sub.4                                                                   22.8 42.8 41-55/0.07                                                                    n.sub.D.sup.24 1.5065                      1AN   CH.sub.3                                                                          CH.sub.2 CCH   20.5 18.8 96.5-100/20                                1AP   CH.sub.3                                                                          3,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                       23.5 27.1 123-129/0.4                                1AQ   CH.sub.3                                                                          CH.sub.2 CH.sub. 2 F                                                                         27.4 28.6 85-89/14                                   1AR   CH.sub.3                                                                          CH.sub.2 CH.sub.2 Cl                                                                         57   64.0 93-108/14                                  __________________________________________________________________________

Following a procedure similar to that described in Example 1, using anappropriate alkanedione of Formula III and an appropriate amine, R₇ NH₂,in refluxing benzene or toluene, the following compounds of Formula Vare prepared.

                  Table 1b                                                        ______________________________________                                        Example    R.sub.6    R.sub.7                                                 ______________________________________                                        1AS        CH.sub.3   3-pyridyl                                               1AT        CH.sub.3   CH.sub.2 CH.sub.2 SC.sub.2 H.sub.5                      1AU        CH.sub.3   4-BrC.sub.6 H.sub.4                                     1AV        CH.sub.3   2,4,6-Cl.sub.3 C.sub.6 H.sub.2                          1AW        CH.sub.3   2-Cl-4-CH.sub.3 C.sub.6 H.sub.3                         1AX        CH.sub.3                                                                                  ##STR24##                                              1AY        CH.sub.3   4-CF.sub.3 C.sub.6 H.sub.4                              1AZ        CH.sub.3   2,4,6-(CH.sub.3).sub.3 C.sub.6 H.sub.2                  1BA        C.sub.3 H.sub.7                                                                          C.sub.6 H.sub.5                                         1BB        iso-C.sub.3 H.sub.7                                                                      C.sub.6 H.sub.5                                         1BC        C.sub.4 H.sub.9                                                                          C.sub.6 H.sub.5                                         1BD        CH.sub.3   cyclohexyl-CH.sub.2                                     1BE        CH.sub.3   CH.sub.2 CH.sub.2N(CH.sub.2).sub.4                      1BF        CH.sub.3   CH.sub.2 CH.sub.2N(CH.sub.2).sub.5                      1BG        CH.sub.3   2-thienyl                                               1BH        CH.sub.3   3-H.sub.2 NCOC.sub.6 H.sub.4                            1BJ        CH.sub.3   3-CH.sub.3 SC.sub.6 H.sub.4                             1BK        C.sub.6 H.sub.5 CH.sub.2                                                                 C.sub.6 H.sub.5                                         1BL        CH.sub.3   9-acridinyl                                             1BM        CH.sub.3   4-(2,1,3-benzothiazolyl)                                1BN        CH.sub.3   2-benzothiazolyl                                        1BP        CH.sub.3   3-carbazolyl                                            1BQ        CH.sub.3   2-benzoxazolyl                                          1BR        CH.sub.3   2-purinyl                                               1BS        CH.sub.3   6-purinyl                                               1BT        CH.sub.3   2-pyrazinyl                                             1BU        CH.sub.3   4-pyrimidinyl                                           1BV        CH.sub.3   2-thiazolyl                                             1BW        CH.sub.3   3-pyrazolyl                                             1BX        CH.sub.3   2-pyrimidinyl                                           1BY        CH.sub.3   6-pyrimidinyl                                           1BZ        CH.sub.3   2-benzimidazolyl                                        1CA        CH.sub.3   2-benzothiazolyl                                        1CB        CH.sub.3   5-indazolyl                                             1CC        CH.sub.3   6-indazolyl                                             1CD        CH.sub.3   7-indazolyl                                             1CE        CH.sub.3   5-isoquinolinyl                                         1CF        CH.sub.3   3-pyridazinyl                                           1CG        CH.sub.3   2-thiadiazolyl                                          1CH        CH.sub.3   5-tetrazolyl                                            1CJ        CH.sub.3   2-thiazolinyl                                           1CK        CH.sub.3   3-(1,2,4-triazinyl)                                     1CL        CH.sub.3   3-(1,2,4-triazolyl)                                     ______________________________________                                    

B. Intermediates of Formula II EXAMPLE 2

A mixture of 260 g. (2.4 moles) of 1,2,5-trimethylpyrrole, 280 g. (4.8moles) of acetone, 185 g. (2.4 moles) of ammonium acetate and 320 g.(4.8 moles) of potassium cyanide in one liter of glacial acetic acid wasstirred and heated under reflux under a nitrogen atmosphere for 2 days.The mixture ws cooled to about 60° C., poured into an ice-water mixturewith stirring, and the solid which separated was dissolved in 3 litersof diethyl ether, the solution washed with water and saturatedbicarbonate, and taken to dryness to give 412 g. of crude product whichwas recrystallized from hexane to give 151 g. of2,4,5,6-tetrahydro-1,2,3,4,6,6-hexamethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 123°-125° C.

EXAMPLE 3

To a solution of 220 g. (4.1 moles) of ammonium chloride, 232 g. (4.0moles) of acetone and 600 ml. of diethyl ether was added with coolingand vigorous stirring a solution of 280 g. (4.3 moles) of potassiumcyanide in 440 ml. of water. The cooling bath was then removed, themixture stirred at room temperature overnight, the organic phaseseparated, and the aqueous phase washed with diethyl ether. The combinedorganic fractions were dried and taken to dryness to give a yellowliquid which was distilled in vacuo to give 162 g. of2-amino-2-methylpropionitrile, b.p. 61°-62° C./20 mm.

A mixture of 119 g. (1.42 moles) of 2-amino-2-methylpropionitrile, 155g. (1.36 moles) of 2,5-hexanedione and 500 ml. of glacial acetic acidwas refluxed under nitrogen for about four days, and the reactionmixture was evaporated to dryness. (With an equimolar amount oftrifluoroacetic acid present, the reaction time can be decreased tothree hours). The residue was taken up in diethyl ether, washedrepeatedly with dilute hydrochloric acid, water, then dilute aqueoussodium bicarbonate, dried over sodium sulfate, and taken to dryness togive a brown solid which was recrystallized from acetonitrile to giveabout 33 g. of2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 130°-140° C., which on sublimation afforded 26.7 g. of the compoundhaving m.p. 150.5°-152.5° C.

EXAMPLE 4

A mixture of 27.2 g. (0.1 mole) of1,1'-hexamethylenebis[2,5-dimethylpyrrole] described in Example 1A, 33.6g. (0.4 mole) of 2-amino-2-methylpropionitrile, 50 g. (0.4 mole) oftrifluoroacetic acid and 200 ml. of glacial acetic acid was heated underreflux for about two and one half hours, then cooled, poured into water,and the gummy solid which separated was filtered, washed with water, andrecrystallized from hot acetonitrile to give 14.3 g. of2,2'-hexamethylenebis[2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile],m.p. 227.5°-229.5° C.

Following a procedure similar to that described in Example 4, using anappropriate 1-R₇ -2,5-di-R₆ -substituted pyrrole of Formula V describedabove, the following2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitriles of Formula IIwere prepared where, in each instance, R₃, R₄, and R₅ are CH₃.

                                      Table 4a                                    __________________________________________________________________________    Example                                                                            R.sub.6                                                                           R.sub.7    Wt. V                                                                              Wt. II                                                                             m.p. (° C.)/Solvent                      __________________________________________________________________________    4A   CH.sub.3                                                                          CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                        40   40   92-94/methanol                                  4B   CH.sub.3                                                                          4-NH.sub.2 SO.sub.2 C.sub.6 H.sub.4                                                      57   57   255-257/ethanol                                 4C   CH.sub.3                                                                          C.sub.6 H.sub.5                                                                          17.1 24.5 115-117                                         4D   CH.sub.3                                                                          C.sub.2 H.sub.5                                                                          72   42   methanol                                        4E   CH.sub.3                                                                          C.sub.3 H.sub.7                                                                          64   64   75-77/hexane                                    4F   CH.sub.3                                                                          4-CH.sub.3 OC.sub.6 H.sub.4                                                              162  74   isopropanol                                     4G   CH.sub.3                                                                          4-CH.sub.3 C.sub.6 H.sub.4                                                               93   140                                                  4H   CH.sub.3                                                                          4-ClC.sub.6 H.sub.4                                                                      147  125  136-139/isopropanol                             4J   CH.sub.3                                                                          3-ClC.sub.6 H.sub.4                                                                      106.5                                                                              81.4 isopropanol/methanol                            4K   CH.sub.3                                                                          2-pyridyl  93   87                                                   4L   CH.sub.3                                                                          3-CH.sub.3 C.sub.6 H.sub.4                                                               100  95   acetonitrile                                    4M   CH.sub.3                                                                          2-ClC.sub.6 H.sub.4                                                                      92   117                                                  4N   CH.sub.3                                                                          2-CH.sub.3 C.sub.6 H.sub.4                                                               93   102.5                                                                              b.p. 139-142/0.25-30                            4P   CH.sub.3                                                                          4-FC.sub.6 H.sub.4                                                                       94   88   isopropanol                                     4Q   CH.sub.3                                                                          4-(CH.sub.3).sub.2 NC.sub.6 H.sub.4                                                      57   54   methanol                                        4R   CH.sub.3                                                                          4-HOC.sub.6 H.sub.4                                                                      155  157                                                  4S   CH.sub.3                                                                          4-CH.sub.3 CONHC.sub.6 H.sub.4                                                           68   47   acetonitrile                                    4T   CH.sub.3                                                                          iso-C.sub.3 H.sub.7                                                                      49.7 25.6 76-80/hexane                                    4U   CH.sub.3                                                                          CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                       66.1 103.1                                                4V   CH.sub.3                                                                          CH.sub.2 COOC.sub.2 H.sub.5                                                              72.4 55.3 60-62/cyclohexane                               4W   CH.sub.3                                                                          cyclohexyl 88   81   isopropanol                                     4X   CH.sub.3                                                                          cyclopropyl                                                                              27.4 24.7 isopropanol                                     4Y   CH.sub.3                                                                          cyclopentyl                                                                              32.8 38.2 98-102/isopropanol-                                                           H.sub.2 O                                       4Z   CH.sub.3                                                                          CH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2                                               8.4  1.3  b.p. 115/0.05;                                                                n.sub.D.sup.25 1.5095                           4AA  CH.sub.3                                                                          CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O                                           20.8 9.4  103-105/hexane                                  4AB  CH.sub.3                                                                          CH.sub.2 CH.sub.2 CH.sub.2 OH                                                            30.6 1.8  100-101/pentane                                 4AC  CH.sub.3                                                                          cyclobutyl 18.2 9.5  95-98                                           4AD  CH.sub.3                                                                          4-O.sub.2 NC.sub.6 H.sub.4                                                               20.8 12.5 206-208.5                                       4AE  CH.sub.3                                                                          sec.-C.sub.4 H.sub.9                                                                     30.3 40.0 b.p. 98/0.15-104/0.35                           4AF  CH.sub.3                                                                          iso-C.sub.4 H.sub.9                                                                      15.1 18.6 b.p. 102-107/0.25                               4AG  CH.sub.3                                                                           ##STR25## 9.75 5.1  158-161                                         4AH  CH.sub.3                                                                          4-C.sub.2 H.sub.5 OC.sub.6 H.sub.4                                                       43.0 35.3 138-140/ether-pentane                           4AJ  CH.sub.3                                                                          3-CF.sub.3 C.sub.6 H.sub.4                                                               42.5 6.9  b.p. 140-155/0.08                               4AK  CH.sub.3                                                                          CH.sub.2 CCH                                                                             18.8 22.9 106-106.5/cyclohexane                           4AL  CH.sub.3                                                                          3,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                   23.1 23.4                                                 4AM  CH.sub.3                                                                          CH.sub.2 CH.sub.2 F                                                                      28.6 17.7 94-95/cyclohexane                               4AN  CH.sub.3                                                                          CH.sub.2 CH.sub.2 Cl                                                                     60   54.9 101-103/isopropanol                             4AP  C.sub.2 H.sub.5                                                                   C.sub.6 H.sub.5                                                                          5.9  11.7 viscous oil                                     __________________________________________________________________________

Following a procedure similar to that described in Example 4, using anappropriate 1-R₇ -2,5-di-R₆ -substituted-pyrrole of Formula V describedabove and 2-amino-2-methylpropionitrile, the following2,4,5,6-tetrahydrocyclopenta[c]-pyrrole-4-carbonitriles of Formula IIare prepared where, in each instance, R₃, R₄, and R₅ are CH₃.

                  Table 4b                                                        ______________________________________                                        Example    R.sub.6     R.sub.7                                                ______________________________________                                        4AQ        CH.sub.3    3-pyridyl                                              4AR        CH.sub.3    CH.sub.2 CH.sub.2 SC.sub.2 H.sub.5                     4AS        CH.sub.3    4-BrC.sub.6 H.sub.4                                    4AT        CH.sub.3    2,4,6-Cl.sub.3 C.sub.6 H.sub.2                         4AU        CH.sub.3    2-Cl-4-CH.sub.3 C.sub.6 H.sub.3                        4AV        CH.sub.3                                                                                   ##STR26##                                             4AW        CH.sub.3    4-CF.sub.3 C.sub.6 H.sub.4                             4AX        CH.sub.3    2,4,6-(CH.sub.3).sub.3 C.sub.6 H.sub.2                 4AY        C.sub.3 H.sub.7                                                                           C.sub.6 H.sub.5                                        4AZ        iso-C.sub.3 H.sub.7                                                                       C.sub.6 H.sub.5                                        4BA        C.sub.4 H.sub.9                                                                           C.sub.6 H.sub.5                                        4BB        CH.sub.3    cyclohexyl-CH.sub.2                                    4BC        CH.sub.3    CH.sub.2 CH.sub.2 N(CH.sub.2).sub.4                    4BD        CH.sub.3    CH.sub.2 CH.sub.2 N(CH.sub.2).sub.5                    4BE        CH.sub.3    2-thienyl                                              4BF        CH.sub.3    4-HOOCC.sub.6 H.sub.4                                  4BG        CH.sub.3    3-H.sub.2 NCOC.sub.6 H.sub.4                           4BH        CH.sub.3    3-CH.sub.3 SC.sub.6 H.sub.4                            4BJ        C.sub.6 H.sub.5 CH.sub.2                                                                  C.sub.6 H.sub.5                                        4BK        CH.sub.3    9-acridinyl                                            4BL        CH.sub.3    4-(2,1,3-benzothiadia-                                                        zolyl)                                                 4BM        CH.sub.3    2-benzothiazolyl                                       4BN        CH.sub.3    3-carbazolyl                                           4BP        CH.sub.3    2-benzoxazolyl                                         4BQ        CH.sub.3    2-purinyl                                              4BR        CH.sub.3    6-purinyl                                              4BS        CH.sub.3    2-pyrazinyl                                            4BT        CH.sub.3    4-pyrimidinyl                                          4BU        CH.sub.3    2-thiazolyl                                            4BV        CH.sub.3    3-pyrazlyl                                             4BW        CH.sub.3    2-pyrimidinyl                                          4BX        CH.sub.3    6-pyrimidinyl                                          4BY        CH.sub.3    2-benzimidazolyl                                       4BZ        CH.sub.3    2-benzothiazolyl                                       4CA        CH.sub.3    5-indazolyl                                            4CB        CH.sub.3    6-indazolyl                                            4CC        CH.sub.3    7-indazolyl                                            4CD        CH.sub.3    5-isoquinolinyl                                        4CE        CH.sub.3    3-pyridazinyl                                          4CF        CH.sub.3    2-thiadiazolyl                                         4CG        CH.sub.3    5-tetrazolyl                                           4CH        CH.sub.3    2-thiazolinyl                                          4CJ        CH.sub.3    3-(1,2,4-triazinyl)                                    4CK        CH.sub.3    3-(1,2,4-triazolyl)                                    ______________________________________                                    

EXAMPLE 5

In a separate run following the procedure described above in Example 4,in which approximately a 1 kg. batch of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitriledescribed above in Example 4C was prepared, a sample of a by-productweighing approximately 100 g. was isolated, and the latter wasrecrystallized from toluene to give 69 g. of3,3,3',3',4,4',6,6'-octamethyl-5,5'-diphenyl-1,1'-spirobis(cyclopenta]4,5-c]pyrrole),m.p. 210°-121° C.

The latter, on reaction with two molar equivalents each of acetone andammonium acetate and four molar equivalents of potassium cyanide inglacial acetic acid affords2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,identical with that described in Example 4C above.

EXAMPLE 6

A mixture of 9.5 g. (0.1 mole) of 2,5-dimethylpyrrole and a suspensionof 7 g. (0.1 mole) of potassium cyanide in 9 ml. of water and 18 ml. ofacetone was stirred vigorously with external cooling and neutralizedfirst with about 10 ml. of concentrated hydrochloric acid and thenacidified with an additional 3 ml. of concentrated hydrochloric acid.The mixture was then heated at 50° C. for 5 hours and poured into 500ml. of water. The solid gummy material which separated was collected,washed with water, then taken into diethyl ether, and the organicsolution washed with water, then sodium bicarbonate, then brine, driedand taken to dryness to give a solid material, which was recrystallizedfrom cyclohexane to give two crops totaling 5.0 g. of3,3,3',3',4,4',6,6'-octamethyl-1,1'-spirobis(cyclopenta[4,5-c]pyrrole),m.p. 184-190° C. and 183-188° C.

The latter (2.2 g., 0.007 mole), together with 0.82 g. (0.014 mole) ofacetone, 1.1 g (0.014 mole) of ammonium acetate and 1.9 g. (0.028 mole)of potassium cyanide in 10 ml. of glacial acetic acid was heated underreflux under a nitrogen atmosphere for eighteen hours. The mixture wasthen poured into water, and the solid which separated was dissolved indiethyl ether, washed first with water, then with sodium bicarbonate,then with saturated brine, dired and the solution taken to dryness. Theresidual solid was triturated with cyclohexane to give 2.1 g. of2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 146-150° C., identical with the material described above in Example3.

EXAMPLE 7

To a solution prepared by heating 23.2 g. (0.55 mole) of a 67% mineraloil dispersion of sodium hydride in 200 ml. of anhydrousdimethylsulfoxide was added 50.5 g. (0.25 mole) of the2,4,5,6-tetrahydro-1,3,4,6,6-pnetamethylcyclopenta[c]-pyrrole-4-carbonitrile described above in Example 3. The mixture wasstirred under nitrogen for about two hours, cooled to 15° C., andtreated with 39.5 g. (0.25 mole) of 3-chloro-N,N-dimethylpropylaminehydrochloride. When the foaming had subsided, the mixture was stirred atroom temperature overnight, poured into water, and the gummy solid whichseparated was taken into diethyl ether and the solution washed firstwith water, then with saturated brine, dried and taken to dryness togive 69 g. of a solid which was recrystallized once from hexane and oncefrom isopropanol to give 29 g. of2-[3-(dimethylamino)propyl]-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 90.5°-91.0° C.

Following a procedure similar to that described in Example 7, using anappropriate 2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrile ofFormula II where R₇ is hydrogen, the following2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrilesof Formula II were prepared where, in each instance, R₃, R₄, R₅ and R₆are each CH₃. (The abbrevitions abbreviations and Prod. representstarting material and product, respectively).

                                      Table 7                                     __________________________________________________________________________    Example                                                                            R.sub.7  Wt. II (S.M.)                                                                        Wt. II (Prod.)                                                                        m.p. (° C.)/Solvent                       __________________________________________________________________________    7A   CH.sub.2 C.sub.6 H.sub.5                                                               50.5   49      86-88/methanol                                   7B   C.sub.4 H.sub.9                                                                        40.4   34.3    53-55/pentane                                    7C   cyclopropyl-CH.sub.2                                                                   40.4   33.2    90-92/pentane                                    __________________________________________________________________________

EXAMPLE 8

To a solution of 20.2 g. (0.1 mole) of2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,described above in Example 3, in 100 ml. of dioxane was added 5.6 g.(0.11 mole) of acrylonitrile and 6.4 ml. of a 35% solution ofbenzyltrimethyl ammonium hydroxide (Triton B) in methanol, and themixture was stirred at room temperature under nitrogen overnight. Themixture was then poured into ice water, acidified with dilutehydrochloric acid, and the solid which separated was washed with water,dried and recrystallized from ethanol to give 14.8 g. of2-(2-cyanoethyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 169°-170° C.

EXAMPLE 9

A solution of 27.8 g. (0.1 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile(described above in Example 4C) dissolved in 400 ml. of diethyl etherwas cooled to 0° C. and treated dropwise with stirring with a solutionof 81.0 g. (0.6 mole) of sulfuryl chloride in 100 ml. of diethyl ether,and the solution was stirred at room temperature for several hours. Themixture was then poured into ice water, extracted with ether, and thecombined ether extracts dried and taken to dryness to give 42 g. of agummy solid which was triturated with hot diethyl ether to give 23.5 g.of2-phenyl-2,4,5,6-tetrahydro-1,3-bis-dichloromethyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 186°-188.5° C.

A solution of the latter (36.0 g., 0.087 mole) dissolved in 400 ml. of50% aqueous ethanol was refluxed for one hour and then cooled. The solidwhich separated was collected and dissolved in chloroform, and theorganic solution washed once with water and once with saturated sodiumbicarbonate, dried, and taken to dryness to give 28 g. of crude materialwhich was recrystallized from isopropanol to give 19.8 g. of2-phenyl-2,4,5,6-tetrahydro-1,3-diformyl-4,6,6-trimethycyclopenta[c]pyrrole-4-carbonitrile,m.p. 135°-136.5° C.

EXAMPLE 9A

Following a procedure similar to that described in Example 9, 1 kg. (3.6moles) of2-phenyl-2,4,5,6-tetrahydro1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,described in Example 4C, in 12.5 liters of carbon tetrachloride wasreacted with 585 ml. (7.2 moles) of sulfuryl chloride to give 862 g. of2-phenyl-2,4,5,6-tetrahydro-1,3-bis-chloromethyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 123°-126° C. (from cyclohexane). The latter (800 g., 2.5 moles) washydrolyzed in a solution of 410 g. (5.0 moles) of anhydrous sodiumacetate in 8.1 liters of trifluoroacetic acid at a temperature of from25° C. to 36° C., and the product was recrystallized from isopropanol togive 362 g. of 2-phenyl-2,4,5,6-tetrahydro-3-formyl-1,4,6,6-tetramethylcyclopenta[c]-pyrrole-4-carbonitrile, m.p. 132°-135°C.

The mother liquors were recovered, evaporated to dryness and treatedwith 90% aqueous sulfuric acid in the manner described in Example 20below. There was thus obtained2-phenyl-2,4,5,6-tetrahydro-1-formyl-3,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide,identical with the compound described in Example 20AZ.

EXAMPLE 10

1-Phenyl-2,5-dimethylpyrrole, described above in Example 1D (124 g.,0.74 mole), in 200 ml. of ethylene dichloride was reacted with 58.4 g.(0.8 mole) of dimethylformamide and 123 g. (0.8 mole) of phosphorusoxychloride in the presence of 550 g. (4.0 moles) of sodium acetatetrihydrate in 720 ml. of water using the procedure described in OrganicSyntheses, Coll. Vol. 4, page 831 (1963), John Wiley and Sons, New York.The crude product was recrystallized from methanol to give 112.5 g.1-phenyl-2,5-dimethyl-3-formylpyrrole, m.p. 89°-91° C.

A suspension of 26.2 g. (0.62 mole) of a 57% mineral oil dispersion ofsodium hydride in 200 ml. of diemthylformamide was prepared and treatedportionwise with 116 g. (0.59 mole) of diethoxy phosphonoacetonitrile in100 ml. of dimethylformamide. When the exothermic reaction had subsided,the mixture was treated with a solution of 112.5 g. (0.57 mole) of theabove-described 1-phenyl-2,5-dimethyl-3-formylpyrrole in 600 ml. ofdimethylformamide. When the reaction had subsided, the reaction mixturewas poured into water, filtered, and the solid material recrystallizedfrom methanol to give 61.5 g. of1-phenyl-2,5-dimethylpyrrole-3-acrylonitrile, m.p. 145°-147.5° C.

The latter (10.0 g., 0.045 mole) dissolved in 250 ml. of methanol wasreduced under an initial hydrogen pressure of 50 psi at room temperatureover 2 g. of a 10% palladium-on-charcoal catalyst. When reduction wascomplete, the catalyst was removed by filtration, the filtrate taken todryness, and the solid residue recrystallized from cyclohexane to give6.65 g. of 3-(1-phenyl-2,5-dimethyl-3-pyrrole)propionitrile, m.p.83.5°-85.5° C.

The latter, on refluxing in ethanolic potassium hydroxide and isolationfrom a slightly acid medium, affords3-(1-phenyl-2,5-dimethyl-3-pyrrole)propionic acid.

3-(1-Phenyl-2,5-dimethyl-3-pyrrole)propionic acid was also obtained asfollows: To a suspension of 9.6 g. (0.2 mole) of a 50% mineral oildispersion of sodamide in 400 ml. of 1,2-dimethoxyethane was added 49.2g. (0.22 mole) of ethyl diethoxyphosphonoacetate, and the mixture wasstirred at ambient temperature for fifteen minutes, cooled to 0-5° C.and treated with 39.8 g. (0.2 mole) of1-phenyl-2,5-dimethyl-3-formylpyrrole. The mixture was stirred for onehour at 35°-40° C., then for 10 hours at 0.5° C., poured onto ice andextracted with diethyl ether. The ether extracts, on drying andevaporation to dryness, afforded 48.8 g. of ethyl3-(1-phenyl-2,5-dimethyl-3-pyrrole)acrylate. Reduction of 42.7 g. (0.16mole) of the latter in 250 ml. of ethanol over 1 g. of 10%palladium-on-charcoal in a Parr shaker afforded 53 g. of ethyl3-(1-phenyl-2,5-dimethyl-3-pyrrole)propionate, which on saponificationwith alkali afforded 3-(1-phenyl-2,5-dimethyl-3-pyrrole)propionic acid.

A mixture of 1 g. (0.004 mole) of the latter in 10 g. of polyphosphoricacid was heated at 95° C. for 12 hours, and then poured into ice/waterand extracted with ether. The ether extracts, on washing, drying andevaporation to dryness, afforded a solid which was recrystallized fromcyclohexane to give 700 mg. of4-oxo-1,3-dimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole, m.p.71°-73° C.

The latter (2.0 g., 0.0089 mole) was dissolved in tetrahydrofuran, andthe solution was treated with a solution of 0.0097 mole of methylmagnesium bromide in tetrahydrofuran and stirred at 0°-5° C. for 12hours, then at ambient temperature for 4 hours. The mixture was thenpartitioned between water and ether and the ether extracts, on washing,drying and evaporation to dryness afforded4-hydroxy-1,3,4-trimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrroleas an oil.

The latter, along with 2.6 g. (0.04 mole) of potassium cyanide and 4 g.(0.04 mole) of potassium acetate, was dissolved in 40 ml. of glacialacetic acid and the solution refluxed for 2 hours and then partitionedbetween water and ether. The ether extracts, on washing, drying andevaporation to dryness, afforded an oil which was dissolved in hexaneand chromatographed on silica, eluting with hexane. There was thusobtained 500 mg. of1,3,4-trimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrileas an oil.

EXAMPLE 10A

1,2,5-Trimethylpyrrole (109 g., 1.0 mole) in 250 ml. of ethylenedichloride was reacted with 80 g. (1.1 moles) of dimethylformamide and169 g. (1.1 moles) of phosphorus oxychloride in the presence of 750 g.(5.5 moles) of sodium acetate trihydrate in one liter of water using theprocedure described in Organic Syntheses, Coll. Vol. 4, page 831, (1963)John Wiley and Sons, New Yor, and the crude product was recrystallizedfrom acetonitrile to give 71.1 g. of 1,2,5-trimethyl-3-formylpyrrole,m.p. 97°-99° C.

A suspension of 9.3 g. (0.22 mole) of a 57 % mineral oil dispersion ofsodium hydride in 200 ml. of anhydrous 1,2-dimethoxyethane was treateddropwise with 37.5 g. (0.2 mole) of diethoxyphosphonoacetonitrile, andthe mixture was stirred until evolution of hydrogen had ceased. Theresulting solution was then treated with a solution of 27.4 g. (0.2mole) of the above 1,2,5-trimethyl-3-formylpyrrole in 250 ml. of1,2-dimethoxyethane. When the exothermic reaction had subsided, themixture was heated to 80° C., then allowed to cool to room temperature,diluted with 100 ml. of dimethylformamide, heated to reflux, then cooledand poured into ice water. The solid which separated was collected andrecrystallized from methanol to give 14 g. of1,2,5-trimethylpyrrole-3-acrylonitrile, m.p. 148.5°-150.5° C.

Reduction of the latter with hydrogen over a palladium-on-charcoalcatalyst; alkaline saponification of the resulting3-(1,2,5-trimethyl-3-pyrrole) propionitrile; cyclization of theresulting 3-(1,2,5-trimethyl-3-pyrrole)propionic acid withpolyphosphoric acid; reaction of the resulting4-oxo-1,2,3-trimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole with methylmagnesium bromide; and reaction of the resulting4-hydroxy-1,2,3,4-tetramethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrolewith potassium cyanide and potassium acetate in glacial acetic acidusing the procedure described above in Example 10 affords1,2,3,4-tetramethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrile.

EXAMPLE 10B

A solution of 1.5 g. (0.067 mole) of4-oxo-1,3-dimethyl-2-phenyl-2,4,5,6,-tetrahydrocyclopenta[c]pyrrole,described above in Example 10, and 254 mg. (0.0067 mole) of sodiumborohydride in 15 ml. of ethanol was stirred for 16 hours at 0°-5° C.,then for an additional eight hours at ambient temperature and pouredinto ice/water. The mixture was extracted with ether, and the etherextracts were dried and evaporated to dryness to give4-hydroxy-1,3-dimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrroleas an oil.

The latter, on reaction with potassium cyanide and potassium acetate inglacial acetic acid affords1,3-dimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrile.

EXAMPLE 11

A mixture of 25.3 g. (0.078 mole) of2-(4-acetylaminophenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,described above in Example 4S, and 7.5 g. (0.12 mole) of 86% aqueouspotassium hydroxide in 20 ml. of water and 400 ml. of ethylene glycolwas heated under reflux with stirring overnight and the mixture thenpoured into an ice/water mixture. The solid which separated wascollected and recrystallized from isopropanol to give 7 g. of2-(4-aminophenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 175°-183° C.

EXAMPLE 12

A mixture of 20 g. (0.066 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3-diformyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile(described above in Example 9), 200 ml. of diethylene glycol monoethylether and 2.5 g. of 10% palladiumon charcoal was refluxed under nitrogenwith stirring for twenty-four hours, then cooled, diluted with methanolto 400 ml. and filtered. The filtrate was taken to dryness, and theresidue diluted with water and extracted with ethyl acetate. The ethylacetate layer was separated, washed four times with water, once withbrine, dried, and taken to dryness to give 20.5 g. of a slightly gummymaterial, which was recrystallized from isopropanol to give 6.5 g. of2-phenyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 139°-141° C.

EXAMPLE 13

A solution of 11.1 g. (0.04 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile(described in Example 4C) in 160 ml. of absolute ether was cooled to-10° C. and treated dropwise with vigorous stirring with 28.6 g. (0.27mole) of sulfuryl chloride. The mixture was allowed to stand at roomtemperature for an additional 32 hours, and the solid which separatedwas then collected to give 7.5 g. of2-phenyl-1-dichloromethyl-3-trichloromethyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 181°-184° C.

The 4-carbonitrile thus obtained (7.5 g., 0.017 mole) dissolved in 50ml. of trifluoroacetic acid was treted with a solution of 13.9 g. (0.08mole) of silver acetate in 120 ml. of trifluoroacetic acid. The mixturewas stirred at room temperature for 20 minutes, refluxed under nitrogenfor 15 minutes, and the mixture filtered to remove the solidprecipitate. The filtrate was taken to dryness in vacuo, the residuedissolved in ethyl acetate, and the solution was washed first withwater, then with brine, dried, and taken to dryness to give 9.2 g. of apale brown gum which was crystallized from isopropanol to give 5.4 g. of2-phenyl-1-formyl-3-carboxy-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]-pyrrole-4-carbonitrile,m.p. 209°-211° C.

The latter (2.24 g., 0.006 mole) was heated in an oil bath undernitrogen at 240° C. for about 16 hours, and the residue wasrecrystallized from methanol to give 533 mg. of2-phenyl-1-formyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 124°-126° C.

EXAMPLE 13A

Following a procedure similar to that described in Example 13, 125 g.(0.42 mole) of2-(4-fluorophenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,described in Example 4P was reacted with 314 g. (2.32 moles) of sulfurylchloride to give 74.6 g. of2-(4-fluorophenyl)-1-dichloromethyl-3-trichloromethyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile.

The latter (50.2 g., 0.107 mole) was reacted with 89.5 g. (0.535 mole)of silver acetate in 1600 ml. of trifluoroacetic acid to give 28.8 g. of2-(4-fluorophenyl)-1-formyl-3-carboxy-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile.

The latter (15 g., 0.04 mole) was heated in an oil bath at 115°-120° C.under a nitrogen atmosphere for 1 hour and the product recrystallizedfrom ethyl acetate to give 5.8 g. of2-(4-fluorophenyl)-1-formyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 165°-168° C.

EXAMPLE 13B

Following a procedure similar to that described in Example 13, 49.6 g.(0.17 mole) of2-benzyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,described in Example 7A, was reacted with 91.8 g. (0.68 mole) ofsulfuryl chloride in 500 ml. of ether to give 33.3 g. of2-benzyl-1,3-bis-dichloromethyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 139°-141° C.

The latter (47.4 g., 0.11 mole) was hydrolyzed by refluxing in 500 ml.of 50% aqueous ethanol for 1 hour and the product recrystallized oncefrom ethanol and once from ethyl acetate/hexane to give 4.9 g. of2-benzyl-1,3-diformyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile,m.p. 107°-109° C

EXAMPLE 13C

Another procedure for introducing a carboxylic acid group at the 1- or3-positions of the compounds of Formula II is illustrated by thefollowing:

To a solution of 16.65 g. (0.06 mole) of 2-phenyl-1-formyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile(described in Example 13) in 120 ml. of pyridine and 90 ml. of water atsteam bath temperature was added, over a period of 50 minutes, 18.9 g.(0.12 mole) of potassium permanganate. The mixture was then refluxed foran hour, cooled, poured into an aqueous suspension of sodiummetabisulfite, acidified to pH 3 with hydrochloric acid, filtered andthe solid filter dissolved in benzene. The benzene solution was washedwith water, dried, evaporated to dryness and the residue recrystallizedfrom acetonitrile to give 6.2 g. of2-phenyl-1-carboxy-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta-[c]pyrrole-4-carbonitrile.

The latter was converted to the methyl ester by addition of 7.25 g.(0.025 mole) of the acid to a stirred suspension of 1.33 g. (0.028 mole)of a 50% mineral oil dispersion of sodium hydride in 50 ml. ofdimethylformamide followed by addition of 1.72 ml. (0.028 mole) ofmethyl iodide. After stirring the reaction mixture for 12 hours, themixture was poured into ice water, and the solid which separated wascollected, dissolved in methylene dichloride, and the solution washedwith aqueous sodium bicarbonate, dried and evaporated to dryness to give7.25 g. of2-phenyl-1-carbomethoxy-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile.

EXAMPLE 13D

Following a procedure similar to that described in Example 13C, 17.48 g.(0.06 mole) of2-phenyl-3-formyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carbonitrilewas oxidized with 18.9 g. (0.12 mole) of potassium permanganate in 120ml. of pyridine and 90 ml. of water to give 4.03 o2-phenyl-3-carboxy-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carbonitrilewhich was esterified by reaction of 9.83 g. (0.032 mole) of the acidwith 1.713 g. (0.035 mole) of a 50% mineral oil dispersion of sodiumhydride followed by 2.23 ml (0.036 mole) of methyl iodide. There wasthus obtained 4.18 g. of2-phenyl-3-carbomethoxy-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carbonitrile.

EXAMPLE 14

A mixture of 7.9 g. (0.04 mole) of 1,1,2,2-tetraacetylethane, 3.7 g.(0.04 mole) of aniline and 3.3 g. (0.04 mole) of sodium acetate in 50ml. of glacial acetic acid was refluxed for 1 hour and then evaporatedto dryness in vacuo. The residue was poured into water, the mixtureextracted with chloroform, and the chloroform extracts, after drying,were taken to dryness. The residue was slurried with pentane to give adark brown crystalline material which was dissolved in benzene andchromatographed on activated magnesium silicate. The major product fromthe eluate gave yellow crystals on evaporation, which were slurried inpentane to give 4.1 g. of 1-phenyl-2,5-dimethyl-3,4-diacetylpyrrole,m.p. 100°-103° C.

A solution of 10.2 g. (0.04 mole) of1-phenyl-2,5-dimethyl-3,4-diacetylpyrrole in 100 ml. of tetrahydrofuranwas added dropwise with stirring at 0° C. to a solution of 0.15 mole ofmethyl magnesium bromide in 50 ml. of anhydrous diethyl ether. Themixture was then refluxed for a half hour, cooled, diluted with waterand extracted with ether. The combined organic extracts, on drying andevaporation to dryness, afforded an oil which solidified on triturationwith hexane. The solid was collected and extracted several times withhot hexane to give 2.5 g. of crude hexane soluble material and 1.9 g. ofhexane insoluble material. The hexane soluble and the hexane insolublecrops were each recrystallized from dilute ethanol to give,respectively, 1.7 g. and 1.9 g. samples of1-phenyl-2,5-dimethyl-3,4-di-(2-hydroxy-2-propyl)-pyrrole, m.p.113°-116° C. and 112°-114° C., respectively.

A solution of 1.6 g. (0.006 mole) of1-phenyl-2,5-dimethyl-3,4-di-(2-hydroxy-2-propyl)pyrrole and 0.8 g.(0.012 mole) of potassium cyanide in 30 ml. of glacial acetic acid wasrefluxed for 4 hours, then poured into water and the mixture extractedwith ether. The ether extracts, on washing with water, drying oversodium sulfate, and evaporation to dryness, gave an oil which wasidentified through its n.m.r. and mass spectra as2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitriledescribed above in Example 4C.

EXAMPLE 15

A mixture of 59.4 g. (0.3 mole) of 1,1,2,2-tetraacetylethane, 27.9 g.(0.3 mole) of aniline and 40 g. of sodium acetate in 400 ml. of glacialacetic acid was heated under reflux for 3 hours, then cooled andconcentrated to a small volume in vacuo. The residue was treated withwater, and the solid which separated was collected, washed with water,dried and recrystallized from cyclohexane to give two crops totaling 64g. of 1-phenyl-2,5-dimethyl-3,4-diacetylpyrrole, m.p. 96°-99° C.

The latter (10.2 g., 0.04 mole) in 100 ml. of tetrahydrofuran wastreated at 0° C. with 50 ml. (0.15 mole) of a 3M solution of methylmagnesium bromide in diethyl ether. The solution was heated under refluxfor one-half hour, then cooled, treated with water, and the organiclayer separated and washed with brine. Evaporation of the organicextracts to dryness afforded a solid material which was recrystallizedfrom aqueous ethanol to give two crops (1.7 g. and 1.9 g.) of3,5-dihydro-1,1,3,3,4,6-hexamethyl-5-phenyl-1H-furo[3,4-c]-pyrrole, m.p.113°-116° C. and 112°-114° C., respectively.

A solution of 1.6 g. (0.0059 mole) of the latter and 0.8 g. (0.012 mole)of potassium cyanide in 30 ml. of glacial acetic acid was stirred atroom temperature for about 48 hours and then at reflux temperature forabout seven hours. The mixture was poured into water and the mixtureextracted with diethyl ether. The organic extracts were washed withwater, dried over sodium sulfate, and evaporated to dryness to give abrown oil whose mass spectrum and nuclear magnetic resonance spectrumshowed the product to be largely2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,described above in Example 4C.

EXAMPLE 16

To a solution of 6 g. (0.03 mole) of1-phenyl-2,5-dimethyl-3-acetylpyrrole in 60 ml. of tetrahydrofuran wasadded 15 ml. of a 0.045 molar solution of methyl magnesium bromide inether and the solution maintained at 0°-5° C. for 24 hours. The mixturewas then poured into a saturated solution of ammonium chloride andextracted with ether. The ether extracts, on drying and evaporation todryness afforded 7 g. of1-phenyl-2,5-dimethyl-3-(1-methyl-1-hydroxy)-ethylpyrrole.

A solution of 2.3 g. (0.01 mole) of the latter, 1.3 g. (0.02 mole) ofpotassium cyanide, 1.99 g. (0.02 mole) of potassium acetate and 0.73 ml.(0.01 mole) of acetone in 20 ml. of glacial acetic acid was refluxed for6 hours on a steam bath and then stirred at ambient temperature fortwelve hours. The mixture in a water immiscible solvent was extractedfirst with dilute ammonium hydroxide to remove all acetic acid and thenwith saturated ammonium chloride. Evaporation of the solvent gavematerial which was shown by nmr to consist of 40%1-phenyl-2,5-dimethylpyrrole and 60%2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile.

EXAMPLE 17

A solution of 5.84 g. (0.02 mole) of2-phenyl-3-formyl-1,4,6,6-tetramethyl-2,4,5,6-tetrahydrocyclopenta[c]-pyrrole-4-carbonitrile,described in Example 9A, in 200 ml. of tetrahydrofuran was cooled to -5°C. under nitrogen and then treated with 11.4 ml. of a 2.1 molar solutionof diethyl aluminum cyanide in benzene, the solution stirred for two anda half hours and then poured into 300 g. of ice and 10 ml. of aceticacid. Extraction of the mixture with benzene and concentration of theextracts to dryness after washing and drying gave 5.4 g. of crudeproduct which was triturated several times with benzene and once withhexane to give 4.2 g. of2-phenyl-1,4,6,6-tetramethyl-3-(hydroxycyanomethyl)-2,4,5,6-tetrahydrocyclopenta[c]-pyrrole-4-carbonitrile,m.p. 133°-134° C.

EXAMPLE 18

Reduction of the2-(4-fluorophenyl)-1-formyl-3-carboxy-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]-pyrrole-4-carbonitrileand2-benzyl-1,3-diformyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitriledescribed in Examples 13A and 13B, respectively, with sodium borohydrideusing the procedure described in Example 10B, gave the followingcompounds of Formula II where R₃, R₄ and R₅ are CH₃.

                                      Table 18                                    __________________________________________________________________________    Example                                                                            R.sub.6 (1)                                                                        R.sub.6 (3)                                                                        R.sub.7                                                                             Wt.S.M.                                                                            Wt.Prod.                                                                            m.p. (° C.)/Solvent                    __________________________________________________________________________    18A  CH.sub.2 OH                                                                        COOH 4-FC.sub.6 H.sub.4                                                                  3.4  1.0   188/methanol-water                            18B  CH.sub.2 OH                                                                        CH.sub.2 OH                                                                        C.sub.6 H.sub.5 CH.sub.2                                                            10.0 3.6   172.5-174.5/                                                                  ethanol-benzene                               __________________________________________________________________________

EXAMPLE 19

A solution of 6.12 g. (0.02 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3-diformyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile,described above in Example 9, 2.08 g. (0.02 mole) of2,2-dimethyl-1,3-propanediol and 0.1 g. of p-toluenesulfonic acidhydrate was refluxed under a water separator for about twelve hours andthen washed with dilute sodium bicarbonate. The extracts, on drying andevaporation to dryness, gave 8 g. of crude material which wasrecrystallized from cyclohexane to give 5.7 g. of2-phenyl-1-formyl-4,6,6-trimethyl-3-(5,5-dimethyl-1,3-dioxan-2-yl)-2,4,5,6-tetrahydrocyclopenta[c]-pyrrole-4-carbonitrile,m.p. 175°-177° C.

EXAMPLE 19A

Similarly prepared from 9.19 g. (0.03 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3-diformyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile,3.85 ml. of 2-methylpentane-2,4-diol and 0.1 g. of p-toluenesulfonicacid in 80 ml. of benzene was2-phenyl-1-formyl-4,6,6-trimethyl-3-(4,4,6-trimethyl-1,3-dioxan-2-yl)cyclopenta[c]pyrrole-4-carbonitrile,m.p. 143°-144° C. (6.35 g., from cyclohexane).

II. FINAL PRODUCTS EXAMPLE 20

A mixture of 22 g. (0.10 mole) of2,4,5,6-tetrahydro-1,3,4,6,6-hexamethylcyclopenta[c]pyrrole-4-carbonitrilein 10 ml. of water and 100 ml. of concentrated sulfuric acid was warmedto 85° C., on a steam bath and heated with stirring for about fiveminutes. The resulting dark brown solution was poured into water,basified with 35% aqueous sodium hydroxide until no further solidseparated, and the solid which precipitated was collected, washed withwater, air dried, and recrystallized with charcoaling from ethyl acetateto give 17.3 g. of2,4,5,6-tetrahydro-1,2,3,4,6,6-hexamethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 184.5°-187.5° C.

Following a procedure similar to that described in Example 1, using anappropriate2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile ofFormula II, the following2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]-pyrrole-4-carboxamidesof Formula I were prepared, where in each instance, R₁ and R₂ are eachhydrogen; X is O; and R₃, R₄ and R₅ are each CH₃.

                                      Table 20a                                   __________________________________________________________________________    Example                                                                            R.sub.6 R.sub.7      Wt. II                                                                            Wt. I                                                                              m.p. (° C.)/Solvent                 __________________________________________________________________________    20A  CH.sub.3                                                                              H            60  28  230-233/ethyl acetate                       20B  CH.sub.3                                                                              CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                               29.3                                                                              19  114.5-116/acetonitrile                      20C  CH.sub.3                                                                              --(CH.sub.2).sub.6 --                                                                      45  10.5                                                                              218-221/DMF                                 20D  CH.sub.3                                                                              CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                          56  17.8                                                                              115.5-117.5/cyclo-                                                            hexane                                      20E  CH.sub.3                                                                              4-NH.sub.2 SO.sub.2 C.sub.6 H.sub.4                                                        44  1.8 258-260/methanol                            20F  CH.sub.3                                                                              C.sub.6 H.sub.5                                                                            28  18  140/cyclohexane                             20G  CH.sub.3                                                                              C.sub.2 H.sub.5                                                                            37.2                                                                              15.2                                                                              162-164/ethyl acetate                       20H  CH.sub.3                                                                              C.sub.3 H.sub.7                                                                            40  34.4                                                                              164.5-166.5/isopropanol                     20J  CH.sub.3                                                                              CH.sub.2 C.sub.6 H.sub.5                                                                   24  20.2                                                                              170-171/ethyl acetate                       20K  CH.sub.3                                                                              4-CH.sub.3 OC.sub.6 H.sub.4                                                                70  37  198.5-201/isopropanol                       20L  CH.sub.3                                                                              4-CH.sub.3 C.sub.6 H.sub.4                                                                 58.4                                                                              32  198-202/acetonitrile                        20M  CH.sub.3                                                                              4-ClC.sub.6 H.sub.4                                                                        62.5                                                                              34  165.5-167.5/acetonitrile                    20N  CH.sub.3                                                                              3-ClC.sub.6 H.sub.4                                                                        81.4                                                                              60  139-142/acetonitrile                        20P  CH.sub. 3                                                                             2-pyridyl    86  32  187-189/acetonitrile                        20Q  CH.sub.3                                                                              3-CH.sub.3 C.sub.6 H.sub.4                                                                 60  27.4                                                                              149.5-151.5/methanol                        20R  CH.sub.3                                                                              2-ClC.sub.6 H.sub.4                                                                        116 14.7                                                                              181-183/methanol                            20S  CH.sub.3                                                                              2-CH.sub.3 C.sub.6 H.sub.4                                                                 100 28  159-161/methanol                            20T  CH.sub.3                                                                              4-FC.sub.6 H.sub.4                                                                         88  54  150-151/isopropanol                         20U  CH.sub.3                                                                              4-(CH.sub.3).sub.2 NC.sub.6 H.sub.4                                                        64.2                                                                              31.5                                                                              238-241/DMF                                 20V  CH.sub.3                                                                              4-HOC.sub.6 H.sub.4                                                                        88.2                                                                              31.7                                                                              249-251/methanol                            20W  CH.sub.3                                                                              4-CH.sub.3 CONHC.sub.6 H.sub.4                                                             55  22  236-239/methanol                            20X  CH.sub.3                                                                              CH.sub.2 CH.sub.2 CONH.sub.2                                                               23.9                                                                              4.3 130.5-133/acetone                           20Y  CH.sub.3                                                                              C.sub.4 H.sub.9                                                                            30.7                                                                              7.8 135-137/cyclohexane                         20Z  CH.sub.3                                                                              iso-C.sub.3 H.sub.7                                                                        25.6                                                                              13.5                                                                              156-158/cyclohexane                         20AA CH.sub.3                                                                              CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                         103.1                                                                             21.5                                                                              109-111/hexane                              20AB CHO     C.sub.6 H.sub.5                                                                            10  3.4 164.5-166.5/methanol                        20AC CH.sub.3                                                                              CH.sub.2 COOC.sub.2 H.sub.5                                                                55  33.5                                                                              138-140/ether-                                                                ethanol                                     20AD CH.sub.3                                                                              cyclohexyl   81  31  125-150/isopropanol                         20AE CH.sub.3                                                                              cyclopropyl  12.1                                                                              10.1                                                                              188-192                                     20AF CH.sub.3                                                                              cyclopentyl  6.9 4.6 152-155/cyclohexane                         20AG CH.sub.3                                                                              CH.sub. 2 CH.sub.2 N(CH.sub.3).sub.2                                                       1.9 0.5 110-113/heptane-                                                              hexane                                      20AH CH.sub.3                                                                              CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O                                             9.8 8.6 142-144/hexane                              20AJ CH.sub.3                                                                              CH.sub.2 CH.sub.2 CH.sub.2 OH                                                              2.6                                                 20AK CH.sub.3                                                                              cyclobutyl   9.3 5.5 149-152                                     20AL CH.sub.3                                                                              cyclopropyl-CH.sub.2                                                                       25  10.9                                                                              150-153/ethanol-H.sub.2 O                   20AM H       C.sub.6 H.sub.5                                                                            0.500                                                                             0.500                                                                             192-194/methanol                            20AN CH.sub.3                                                                              sec-C.sub.4 H.sub.9                                                                        40  29.3                                                                              152-154/cyclohexane                         20AP CH.sub.3                                                                              iso-C.sub.4 H.sub.9                                                                        18.5                                                                              12.0                                                                              148.5-151/hexane                            20AQ CH.sub.3                                                                              3,4-(HO).sub.2 C.sub.6 H.sub.3                                                             5.0*                                                                              2.3 129-131/ethyl acetate-                                                        pentane                                     20AR CH.sub.3                                                                              4-C.sub.2 H.sub.5 OC.sub.6 H.sub.4                                                         45  8   212-214/ethanol-H.sub.2 O                   20AS CH.sub.3                                                                              3-CF.sub.3 C.sub.6 H.sub.4                                                                 6.3 4.0 150-153/benzene-                                                              pentane                                     20AT CH.sub.3                                                                              CH.sub.2 C.tbd.CH                                                                          22.6                                                                              14.7                                                                              141-145/cyclohexane                         20AU CH.sub.3                                                                              3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                     23.3                                                                              8.1 182-184/acetonitrile                        20AV CH.sub.3                                                                              CH.sub.2 CH.sub.2 F                                                                        17.7                                                                              11.1                                                                              130-131/benzene-                                                              hexane                                      20AW CH.sub.3                                                                              CH.sub.2 CH.sub.2 Cl                                                                       20.0                                                                              17.3                                                                              145.5-147/benzene-                                                            hexane                                      20AX C.sub.2 H.sub.5                                                                       C.sub.6 H.sub.5                                                                            10.3                                                                              9.0 152-153                                     20AY .sup.+ CHO(1)                                                                         C.sub.6 H.sub.5                                                                            6.3 4.2 190-192/isopropanol                              H(3)                                                                     20AZ CHO(1)  C.sub.6 H.sub.5                                                                            29.8                                                                              1.0 123-126/benzene                                  CH.sub.3 (3)                                                             20BA CHO(1)  4-FC.sub.6 H.sub.4                                                                         6.1 1.0 241 (dec.)/                                      COOH(3)                      methanol                                    20BB CHO(1)  C.sub.6 H.sub.5                                                                            14.0                                                                              7.9 231-232/acetone                                  COOH(3)                                                                  20BC CHO(1)  4-FC.sub.6 H.sub.4                                                                         5.0 3.7 193-196/isopropanol                              H(3)                                                                     20BD CH.sub.3 (1)                                                                          C.sub.6 H.sub.5                                                                            3.0 3.1                                             /ether-hexane                                                                      COOCH.sub.3 (3)                                                          20BE COOCH.sub.3 (1)                                                                       C.sub.6 H.sub.5                                                                            6.0 5.09                                            /ether-hexane                                                                      H(3)                                                                     __________________________________________________________________________     *Starting material was 1-[3,4-(2,2-propylenedioxy)phenyl] compound            described in Example 4AG.                                                     .sup.+ Product is 1-formyl compound prepared from compound of Example 13.

Following a procedure similar to that described in Example 20, using anappropriate 2,4,5,6-tetrahydro-cyclopenta[c]pyrrole-4-carbonitrile ofFormula II in refluxing 90% aqueous sulfuric acid, the followingcompounds of Formula I, where, in each instance, R₁ and R₂ are eachhydrogen; and X is O, are prepared.

                  Table 20b                                                       ______________________________________                                        Ex.   R.sub.3                                                                              R.sub.4                                                                              R.sub.5                                                                            R.sub.6                                                                              R.sub.7                                       ______________________________________                                        20BF  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             4-BrC.sub.6 H.sub.4                           20BG  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2,4,6-Cl.sub.3 C.sub.6 H.sub.2                20BH  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2-Cl-4-CH.sub.3 C.sub.6 H.sub.3               20BJ  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                              ##STR27##                                    20BK  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             4-CF.sub.3 C.sub.6 H.sub.4                    20BL  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2,4,6-(CH.sub.3).sub.3 C.sub.6 H.sub.2        20BM  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             CH.sub.2 CH.sub.2 SC.sub.2 H.sub.5            20BN  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           C.sub.3 H.sub.7                                                                      C.sub.6 H.sub.5                               20BP  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           iso-C.sub.3 H.sub.7                                                                  C.sub.6 H.sub.5                               20BQ  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           C.sub.4 H.sub.9                                                                      C.sub.6 H.sub.5                               20BR  CH.sub.3                                                                             H      H    CH.sub.3                                                                             C.sub.6 H.sub.5                               20BS  CH.sub.3                                                                             H      H    CH.sub.3                                                                             CH.sub.3                                      20BT  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             4-NH.sub.2 C.sub.6 H.sub.4                    20BU  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             cyclohexyl-CH.sub.2                           20BV  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             CH.sub.2 CH.sub.2 N(CH.sub.2).sub.4           20BW  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             CH.sub.2 CH.sub.2 N(CH.sub.2).sub.5           20BX  H      H      H    CH.sub.3                                                                             CH.sub.3                                      20BY  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2-thienyl                                     20BZ  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             4-HOOCC.sub.6 H.sub.4                         20CA  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             3-H.sub.2 NCOC.sub.6 H.sub.4                  20CB  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             3-CH.sub.3 SC.sub.6 H.sub.4                   20CC  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             4-O.sub.2 NC.sub.6 H.sub.4                    20CD  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           C.sub.6 H.sub.5 CH.sub.2                                                             C.sub.6 H.sub.5                               20CE  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             3-pyridyl                                     20CF  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             9-acridinyl                                   20CG  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             4-(2,1,3-benzo-                                                               thiazolyl)                                    20CH  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2-benzothiazolyL                              20CJ  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             3-carbazolyl                                  20CK  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2-benzoxazolyl                                20CL  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2-purinyl                                     20CM  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             6-purinyl                                     20CN  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2-pyrazinyl                                   20CP  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             4-pyrimidinyl                                 20CQ  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2-thiazolyl                                   20CR  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             3-pyrazolyl                                   20CS  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2-pyrimidinyl                                 20CT  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             6-pyrimidinyl                                 20CU  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2-benzimidazolyl                              20CV  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2-benzothiazolyl                              20CW  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             5-indazolyl                                   20CX  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             6-indazolyl                                   20CY  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             7-indazolyl                                   20CZ  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             5-isoquinolinyl                               20DA  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             3-pyridazinyl                                 20DB  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2-thiadiazolyl                                20DC  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             5-tetrazolyl                                  20DD  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             2-thiazolinyl                                 20DE  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             3-(1,2,4-triazinyl)                           20DF  CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           CH.sub.3                                                                             3-(1,2,4-triazolyl)                           ______________________________________                                    

EXAMPLE 21

A mixture of 25 g. (0.09 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitriledescribed above in Example 4C, 100 ml. of absolute ethanol and 25 ml. of35% aqueous sodium hydroxide was refluxed on a steam bath for seventyhours, and the mixture then diluted with 250 ml. of water. The oil whichseparated crystallized on cooling and was collected, washed, and driedto give 17 g. of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta-[c]pyrrole-4-carboxamide,m.p. 123°-130° C. identical with the compound described above in Example20F.

EXAMPLE 22

To a stirred mixture of 10.5 g. (0.24 mole) of a 57% dispersion ofsodium hydride in mineral oil (which was washed and decanted with hexaneto remove the mineral oil) in 100 ml. of dimethylsulfoxide was added asolution of 29.6 g. (0.1 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidedissolved in 200 ml. of dimethylsulfoxide. The reaction mixture wasstirred for about one and a half hours until evolution of hydrogenceased, and then treated dropwise with 35.5 g. (0.25 mole) of methyliodide. After stirring for an additional two hours, the mixture wasdiluted with about 10 ml. of water, poured onto ice, and the whiteprecipitate was removed by filtration. The filtrate was extracted withether, added to an ether solution of the solid, and the combined organicsolution washed several times with water, dried over sodium sulfate, andevaporated to dryness.

The resulting yellow oil (35.3 g.) was dissolved once again in 200 ml.of dimethylsulfoxide, added to a suspension of 6.0 g. of sodium hydridein dimethylsulfoxide, the mixture warmed to 75° C. for above 5 minutes,treated with 18 g. of methyl iodide as above, and then stirred for onehour at room temperature. The reaction mixture, when worked up in themanner described above, afforded 31.3 g. of a yellow oil which slowlycrystallized and which was recrystallized from a methanol/water mixtureto give 27.7 g. of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-N,N-dimethylcarboxamide,m.p. 100-104° C.

Following a procedure similar to that described in Example 22, using anappropriate2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamideand an appropriate lower-alkyl halide, the following compounds ofFormula I, where in each instance R₃, R₄, R₅ and both R₆ groups are eachCH₃, and X is O, are prepared.

                  Table 22                                                        ______________________________________                                        Example  R.sub.1  R.sub.2  R.sub.7                                            ______________________________________                                        22A      CH.sub.3 H        CH.sub.3                                           22B      CH.sub.3 CH.sub.3 CH.sub.3                                           22C      CH.sub.3 H        CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2       22D      CH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2       22E      CH.sub.3 H        CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                  22F      CH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                  22G      CH.sub.3 H        C.sub.6 H.sub.5                                    22H      CH.sub.3 H        2-pyridyl                                          22J      CH.sub.3 CH.sub.3 2-pyridyl                                          ______________________________________                                    

EXAMPLE 23

A 2.53 g. (0.06 mole) portion of a 57% dispersion of sodium hydride inmineral oil was washed free of mineral oil by slurrying and decantationwith hexane, and was then slurried in 40 ml. of dimethylsulfoxide. Tothe mixture was added a solution of 8.8 g. (0.04 mole) of2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide(described above in Example 20A), and the mixture was stirred at roomtemperature for one hour. The mixture was then treated with 8.1 g. (0.06mole) of cyclopropylmethyl bromide, stirred at room temperatureovernight, poured into water, and the mixture extracted with diethylether. The ether extracts, on drying and evaporation to dryness,afforded a brown oil which was chromatographed on silica gel using a 3%isopropanol in ether solution as eluent. There was thus obtained acrystalline material which was slurred with ether/pentane to give 0.55g. of2-cyclopropylmethyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 145°-148° C. identical with that described above in Example 20AL.

EXAMPLE 24

To a solution of 4.45 g. (0.013 mole) of2-phenyl-1-hydroxymethyl-3-carboxy-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamidein 15 ml. of dimethylformamide was added 0.61 g. (0.014 mole) of a 57%mineral oil dispersion of sodium hydride, the mixture was stirred fortwo hours and then treated with 0.8 g. of methyl iodide and stirred atambient temperature for about twelve hours. The mixture was then pouredinto water, and the solid was collected and recrystallized from acetoneto give 2.3 g. of2-phenyl-1-hydroxymethyl-3-carbomethoxy-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 226°-227° C.

EXAMPLE 25

A solution of 3.05 g. (0.01 mole) of2-[3-(dimethylamino)propyl]-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide(described above in Example 20B) in 30 ml. of isopropanol was treatedwith 2.1 g. of methyl iodide, and the mixture was allowed to stand atroom temperature overnight. The material which had separated was thencollected, washed with isopropanol and pentane and dried to give 4.5 g.of2-[3-(dimethylamino)propyl]-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidemethiodide, m.p. 128°-130° C.

A solution of 10.2 g. (0.06 mole) of silver nitrate in 102 ml. of hotwater was treated with a solution of 2.34 g. of sodium hydroxide in 24ml. of hot water. The resulting precipitate was washed five times bydecantation with hot water, then filtered, and the solid added to asolution of about 9 g. (0.02 mole) of2-[3-(dimethylamino)propyl]-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidemethiodide in 60 ml. of water. The mixture was stirred at roomtemperature overnight, then filtered, the filter washed first with hotwater and then with ethanol, the aqueous and the ethanol filtrates beingset aside separately for further work. The ethanol washings wererefiltered, evaporated to dryness, and the solid residue which slowlycrystallized was set aside and combined with organic material obtainedby evaporation to dryness of the aqueous filtrate, heating the solidresidue on a steam bath for three hours under a vacuum pump, extractionof the residue with ethyl acetate and evaporation to dryness of theextracts. The combined material obtained from the aqueous and ethanolwashings was recrystallized from ethyl acetate/pentane to give two cropstotaling 0.7 g. of2-allyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 96°-98° C.

EXAMPLE 26

To a suspension of 1.025 g. of2-phenyl-2,4,5,6-tetrahydro-1,3-diformyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide(described above in Example 20AB) in 10 ml. of ethanol was added withstirring a suspension of 250 mg. of sodium borohydride in ethanol, andthe resulting clear solution was allowed to stand at room temperaturefor two hours. The white crystalline solid which separated wascollected, washed with water and dried to give 645 mg. of product. Thismaterial was combined with that obtained by evaporation to dryness ofthe filtrate from the main product and trituration with water andcollection and drying of the residual solid. There was thus obtained anadditional 344 mg. of2-phenyl-2,4,5,6-tetrahydro-1,3-bishydroxymethyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamideethanolate, m.p. 115°-120° C.

Following a procedure similar to that described in Example 26, thefollowing compounds of Formula I, where in each instance R₁ and R₂ areeach hydrogen and R₃, R₄ and R₅ are each methyl, were prepared.

                                      Table 26                                    __________________________________________________________________________    Example                                                                            R.sub.6    R.sub.7 Wt.S.M.                                                                             Wt.Prod.                                                                            m.p. (° C.)/Solvent                __________________________________________________________________________    26A  CH.sub.2 OH(1)                                                                           C.sub.6 H.sub.5                                                                       2.0   1.59  170-171/ethyl                                  H(3)                           acetate                                   26B  CH.sub.2 OH(1)                                                                           C.sub.6 H.sub.5                                                                       2.3   1.8   184-185                                        CH.sub.3 (3)                                                             26C  CH.sub.2 OH(1)                                                                           4-FC.sub.6 H.sub.4                                                                    3.0   2.0   140-190/ethyl                                  COOH(3)                        acetate                                   26D  CH.sub.2 OH(1)                                                                           C.sub.6 H.sub.5                                                                       6.11  3.37  150-185/ethyl                                  COOH(3)                        acetate                                   26E  CH.sub.2 OH(1)                                                                           4-FC.sub.6 H.sub.4                                                                    2.0   1.3   182-183/benzene                                H(3)                                                                     26F  H(1)       C.sub.6 H.sub.5                                                                       2.8   2.3   158-159/benzene                                CH.sub.2 OH(3)                                                           26G  CH.sub.3 (1)                                                                             C.sub.6 H.sub.5                                                                       401   4.3*  144-147/isopropanol                            CH.sub.2 OCH(CH.sub.3).sub.2 (3)*                                        26H  CH.sub.3 (1)                                                                             C.sub.6 H.sub.5                                                                       1.0   0.9   173-179/aqueous                                CH.sub.2 OH(3)                 ethanol                                   26J  CH.sub.2 OH                                                                              C.sub.6 H.sub.5                                                                       6.2   1.0   116.5-118.5/                                                                  ethanol                                   __________________________________________________________________________     *Obtained by recrystallizing 10 g. (of 444 g. obtained) of the                corresponding 3-hydroxymethyl compound.                                  

EXAMPLE 27

A solution of 10 g. (0.034 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidein 4.5 liters of chloroform was stirred under a high intensity lightwhile bubbling air through the mixture for about 16 hours. The mixturewas then taken to dryness in vacuo and the residue dissolved in benzeneand chromatographed on a column of activated magnesium silicate, theproduct being eluted first with benzene and then with ether. Thecombined eluates were diluted with ethyl acetate, and the solid whichseparated was collected and dried to give 1.05 g. of material which wasshown by its n.m.r. and mass spectra and by chemical analysis to be2-phenyl-3-formyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 201°-204° C.

In another experiment, a solution of 75 mg. of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]-pyrrole-4-carboxamidein a concentration of 1 mg./ml. in chloroform was exposed to sunlightfor above 5 days and the solution then evaporated to a concentration of10 mg./ml., chromatographed on alumina and eluted with 1:1chloroform/methanol. A total of five bands was developed, the first ofwhich yielded 7.8 mg. and the third 33.3 mg. of material both of whosemass spectra showed a molecular ion of 310 (calculated 308.4) and whosen.m.r. spectrum showed the first to be2-phenyl-1-formyl-2,4,5,6-tetrahydro-3,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide,identical with the compound described above in Example 20AZ, and thethird to be the isomeric2-phenyl-3-formyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide.

EXAMPLE 28

2-Phenyl-1-formyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile(described in Example 13) (8.35 g., 0.03 mole) was combined with 4.6 ml.of 85% hydrazine hydrate, 5.25 g. of solid potassium hydroxide and 50ml. of triethylene glycol, and the mixture was refluxed for 11/2 hoursunder nitrogen. The low boiling components were distilled off until thepot temperature reached 205° C., and the mixture was then heated anadditional two hours at that temperature. The mixture was cooled, pouredinto ice water, and extracted with ethyl acetate. The aqueous phase wasacidified with concentrated sulfuric acid, and the solid which separatedwas collected and dried to give 6.2 g. of2-phenyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]-pyrrole-4-carboxylicacid.

The latter (6.18 g., 0.22 mole) was dissolved in 70 ml. oftetrahydrofuran, the solution treated with 4.25 g. (0.026 mole) ofN,N'-carbonyldiimidazole, and the solution stirred for six hours at roomtemperature. A solution of 5 ml. of liquid ammonia in 20 ml. oftetrahydrofuran was then added gradually and the solution stirred atroom temperature for about fifteen hours. The solid which separated wascollected and dissolved in ethyl acetate and the solution washed firstwith dilute alkali, then with brine, dried and taken to dryness. Thepale yellow residual solid was recrystallized once from ethyl acetateand once from methanol to give 1 g. of2-phenyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 185°-202° C.

EXAMPLE 29

A solution of 25 g. of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide(described in Example 20F) in 500 ml. of chloroform containing about0.75% ethanol was stirred at ambient temperature for four days whilebubbling air through the solution. The solution was then taken todryness and the residue eluted with diethyl ether/hexane. There was thusobtained material having m.p. 95°-100° C. whose mass spectrum showed amolecular ion of 384 (calculated 384) and which was shown from itsn.m.r. spectrum to be2-phenyl-1,3-diethoxymethyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide.

The latter on reaction with hydrochloric acid in chloroform afforded amixture which was separated by chromatography into two components, themajor component being2-phenyl-3-formyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]-pyrrole-4-carboxamideand the minor being the isomeric2-phenyl-1-formyl-2,4,5,6-tetrahydro-3,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamidewhich were shown by their mass and n.m.r. spectra to be identical withthe respective compounds described above in Example 27.

EXAMPLE 30

A solution of 2.0 g. (0.006 mole) of the2-phenyl-2,4,5,6-tetrahydro-1,3-bishydroxymethyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamidedescribed in Example 26J in 50 ml. of methanol was treated with 0.11 g.of p-toluenesulfonic acid, the solution was stirred at room temperaturefor an hour and a half and then taken to dryness. The residue wasdissolved in methylene dichloride, the solution washed was saturatedsodium bicarbonate and brine, then dried over sodium sulfate and takento dryness, and the crude product recrystallized from benzene/hexane togive 2.2 g. of2-phenyl-2,4,5,6-tetrahydro-1,3-bismethoxymethyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 168°-169.5° C.

EXAMPLE 31

A mixture of 15.0 g. (0.05 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide(described in Example 20F), 15.0 g. (0.38 mole) of sodium hydroxide, 150ml. of ethylene glycol and 1.0 ml. of water was refluxed in a stainlesssteel round bottom flask for two days. The mixture was then cooled,poured into about one liter of water and acidified with glacial aceticacid. The solid which separated was washed with water and recrystallizedfrom methanol to give 8.0 g. of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxylicacid, m.p. 131°-136° C.

EXAMPLE 32

A stirred solution of 9.0 g. (0.03 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]-pyrrole-4-carboxylicacid (described in Example 31) in 100 ml. of anhydrous tetrahydrofurnawas treated with 5.4 g. (0.033 mole) of carbonyldiimidazole and thesolution stirred at ambient temperature for eighteen hours. Theresulting solution was then treated with 3.5 g. (0.04 mole) of2-dimethylaminoethylamine in 50 ml. of tetrahydrofuran, and the mixturestirred for an additional 6 hours. The solution was then concentrated todryness in vacuo. The residue was partitioned between 200 ml. of waterand 100 ml. of ether, and the organic layer was separated, washed withbrine, dried, and taken to dryness to give 10.8 g. of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-{N-[2-(dimethylamino)-ethyl]}carboxamideas a clear colorless oil.

Following a procedure similar to that described above in Example 32,using the2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxylicacid described in Example 31 and an appropriate tertiaryaminolower-alkylamine, the following compounds of Formula I, where ineach instance R₂ is hydrogen; R₃, R₄, R₅ and R₆ are CH₃ ; R₇ is phenyl;and X is 0 are prepared.

                  Table 32                                                        ______________________________________                                        Example      R.sub.1                                                          ______________________________________                                        32A          CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O                   32B          CH.sub.2 CH.sub.2 N(CH.sub.2).sub.4                              32C          CH.sub.2 CH.sub.2 N(CH.sub.2).sub.5                              ______________________________________                                    

EXAMPLE 33

A suspension of 15.0 g. (0.05 mole) of2-phenyl-2,4,5,6-tretrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxylicacid (described in Example 31) and 6.0 g. (0.06 mole) of potassiumbicarbonate in dimethylformamide was stirred at room temperature for21/2 hours and at 60° C. for a half hour, then cooled and treated with14 g. (0.1 mole) of methyl iodide in dimethylformamide and the mixturestirred overnight. The resulting dark soltuion was taken to dryness invacuo, and the dark residual viscous oil was distilled in vacuo to give5.9 g. of metyl2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxylate,b.p. 130°-132° C./0.05 mm.

EXAMPLE 34

A solution of 9.0 g. (0.03 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxylicacid (described in Example 31) in 50 ml. of anhydrous tetrahydrofuran,and the solution treated with 5.4 g. (0.033 mole) ofcarbonyldiimidazole. The mixture was then treated with a solution of 2.9g. (0.03 mole) of aniline in 25 ml. of tetrahydrofuran, the solutionstirred at room temperature for twenty-four hours, and then taken todryness in vacuo. The residue was partitioned between water and diethylether, and the ether layer was washed with brine, then dried and takento dryness leaving 10.8 g. of a solid residue which was crystallizedtwice from methanol to give 4.7 g. of1-(2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta-[c]pyrrol-4-ylcarbonyl)imidazole, m.p. 134°-136° C.

EXAMPLE 35

A mixture of 29.6 g. (0.1 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide(described in Example 20F) and 0.10 g. of cupric acetate monohydrate in300 ml. of a 4:6 methanol/benzene mixture was stirred under twoatmospheres of oxygen for twenty hours. The resulting black solution wastaken to dryness, and the residual dark semi-solid was dissolved in 300ml. of methylene dichloride and the solution washed with water, thenwith saturated brine, charcoaled, filtered and taken to dryness. Theresidue was recrystallized twice from methanol to give 14.1 g. of amixture of2-phenyl-1-methoxymethyl-2,4,5,6-tetrahydro-3,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamideand2-phenyl-3-methoxymethyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 181°-193° C.

EXAMPLE 36

A mixture of 10 g. (0.032 mole) of2-phenyl-1-formyl-2,4,5,6-tetrahydro-3,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide(described in Example 27) and 1.0 g. of 10% palladium-on-charcoal in 100ml. of 2-(2-ethoxy)-ethoxyethanol was heated to reflux under nitrogenfor eight hours and then cooled and allowed to stand at ambienttemperature for about twelve hours. The catalyst was removed byfiltration, the filtrate poured into water and the mixture extractedwith benzene. The benzene extracts, after washing, drying andevaporation to dryness, gave a yellow gum which was triturated withether and recrystallized from benzene to give 0.9 g. of2-phenyl-2,4,5,6-tetrahydro-3,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 186°-190° C.

EXAMPLE 37

2-Phenyl-1-formyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide(described in Example 20AY) (2.96 g., 0.01 mole) dissolved in 30 ml. ofbenzene and 120 ml. of tetrahydrofuran was reacted with 5.7 ml. (0.012mole) of a 2.1 molar benzene solution of diethyl aluminum cyanide usingthe procedure described above in Example 17. The product was isolated asan amorphous foam which solidified on trituration with benzene. Therewas thus obtained 2.75 g. of2-phenyl-1-(hydroxycyanomethyl)-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamideas the hemi-benzene solvate, slowly decomposes at 120° C., resolidifiesand melts again at 142° C.

EXAMPLE 38

To a solution of 1.0 g. (0.003 mole) of2-phenyl-1-hydroxymethyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta-[c]pyrrole-4-carboxamide(described in Example 26A) in 7 ml. of pyridine was added 570 mg. (0.004mole) of 4-methylbenzoyl chloride. The reaction mixture was refrigeratedfor 2 days, poured into saturated sodium bicarbonate solution, extractedwith methylene dichloride and the organic extracts dried and evaporatedto dryness to give 1.3 g. of residue which was recrystallized from ethylacetate to give 696 mg. of2-phenyl-1-(4-methylbenzoyloxymethyl)-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 200°-204° C.

Using the procedure described in Example 38, the following compounds ofFormula I, were in each case R₁, R₂ and R₆ (3-position) are eachhydrogen, R₃, R₄ and R₅ are each CH₃ and R₇ is C₆ H₅, were prepared from2-phenyl-1-hydroxymethyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamideand acetic anhydride or succinic anhydride.

                                      Table 38                                    __________________________________________________________________________    Example                                                                            R.sub.6 (1)  Wt.S.M.                                                                            Wt.Prod.                                                                            m.p. (° C.)/Solvent                       __________________________________________________________________________    38A  CH.sub.3 COOCH.sub.2                                                                       2.0  1.46  174-176/ethyl                                                                 acetate                                          38B  HOOC(CH.sub.2).sub.2 COOCH.sub.2                                                           2.0  0.9   152-154/ethyl                                                                 acetate-hexane                                   __________________________________________________________________________

EXAMPLE 39

To a solution of 1 g. (0.0025 mole) of2-phenyl-1-(3-carboxypropionyloxymethyl)-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide(described in Example 38B) in 10 ml. of tetrahydrofuran at 0°-5° C. wasadded anhydrous ammonia by passing the gas over the surface of thesolution. The mixture was diluted with ether and the gummy solid whichseparated solidified on scratching to give 1.0 g. of the correspondingammonium salt, m.p. 116°- 118° C.

EXAMPLE 40

To a suspension of 2.96 g. (0.01 mole) of2-phenyl-1-formyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]-pyrrole-4-carboxamide(described in Example 20AY) in 50 ml. of tetrahydrofuran was added 12.9ml. of a 0.16 molar solution of methyl lithium while cooling themixture. After stirring for one hour at 0°-5° C. and for 2 hours atambient temperature, the mixture was poured into ice/aqueous ammoniumchloride and extracted with methylene dichloride. The extracts, ondrying and evaporation to dryness, gave crude product which wasrecrystallized from methylene dichloride-heptane to give 1.91 g. of2-phenyl-1-(1-hydroxyethyl)-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 135°- 145° C.

Using a procedure similar to that described in Example 40 above, thefollowing compounds of Formula I where in each case R₁ and R₂ are eachhydrogen, R₃, R₄ and R₅ are each CH₃ and R₇ is C₆ H₅ were prepared byreaction of an appropriate organo lithium with either the compound ofExample 27 or Example 20AY.

                                      Table 40                                    __________________________________________________________________________    Example                                                                            R.sub.6 (1)                                                                            R.sub.6 (3)                                                                            Wt.S.M.                                                                            Wt.Prod.                                                                            m.p. (° C.)/Solvent                  __________________________________________________________________________    40A  CH.sub.3 CHOHCH.sub.3                                                                           3.0  1.09  108-111/ether-                                                                hexane                                      40B  C.sub.6 H.sub.5 CHOH*                                                                  H        2.96 2.2   198-204/CH.sub.2 Cl.sub.2 -                                                   heptane                                     40C  CH.sub.2 ═CHCHOH                                                                   H        5.92 2.07  144-146/benzene                             40D  CH.sub.3 CHOHC.sub.6 H.sub.5                                                                    6.0  4.12  151-154/aceto-                                                                nitrile                                     40E  CH.sub.3 CHOHCH═CH.sub.2                                                                    6.0  2.88  160-165/ethyl                                                                 acetate                                     40F  C.sub.4 H.sub.9 CHOH                                                                   H        5.92 2.4    75-80/-                                    40G  CH.sub.3 C(CH.sub.3).sub.2 OH                                                                   2.0  0.68  184-186/ether-                                                                hexane                                      40H  C.sub.2 H.sub.5 CHOH                                                                   H        2.96 2.62  155-156/ether-                                                                heptane                                     __________________________________________________________________________     *Phenyl magnesium bromide used as the organo metallic reagent.           

Example 41

Reaction of the2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrilesdescribed in Examples 2, 7, 4A, 4C, 4K, and 8 in an autoclave at150°-160° C. with an ethanol solution saturated with anhydrous ammoniaand anhydrous hydrogen sulfide affords the following compounds ofFormula I where, in each instance, R₁ and R₂ are hydrogen; R₃, R₄, R₅and R₆ are each CH₃ ; and X is S.

                  Table 41                                                        ______________________________________                                        Example      R.sub.7                                                          ______________________________________                                        41A          CH.sub.3                                                         41B          CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                     41C          CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                41D          C.sub.6 H.sub.5                                                  41E          2-pyridyl                                                        41F          CH.sub.2 CH.sub.2 CSNH.sub.2                                     ______________________________________                                    

EXAMPLE 42

Reaction of the ethyl4-carbamoyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-2-acetatedescribed above in Example 20AC with alcoholic sodium hydroxide andisolation of the product from an acid or neutral medium affords4-carbamoyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-2-aceticacid.

EXAMPLE 43

Reaction of the2-(4-carboxyphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidedescribed above in Example 20BZ with methanol in the presence of a smallamount of a mineral acid affords2-(4-carbomethoxyphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]-pyrrole-4-carboxamide.

EXAMPLE 44

Reaction of the2-(3-methylmercaptophenyl)-2,4,5,6-tetrahydro-1,3,4,6,6,-pentamethylcyclopenta[c]pyrrole-4-carboxamidedescribed above in Example 20CB with one molar equivalent of performicacid in acetone at room temperature affords2-(3-methylsulfinylphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide.

EXAMPLE 45

Reaction of2-(3-methylmercaptophenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidedescribed above in Example 20CB with two molar equivalents of performicacid in acetone at room temperature affords2-(3-methylsulfonylphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide.

EXAMPLE 46

Reaction of the2-phenyl-2,4,5,6-tetrahydro-1,3-diformyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamidedescribed above in Example 20AB with two molar equivalents of perbenzoicacid in acetone at room temperature affords2-phenyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamido-1,3-dicarboxylicacid.

EXAMPLE 47

Reaction of the2-phenyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamido-1,3-dicarboxylicacid described above in Example 46 with methanol in the presence of asmall amount of a mineral acid affords dimethyl2-phenyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]-pyrrole-4-carboxamido-1,3-dicarboxylate.

EXAMPLE 48

Reaction of1-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrilewith one molar equivalent of diisobutyl aluminum hydride intetrahydrofuran, and, without isolation of the product, oxidation of theresulting material with oxygen affords2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide.

Data obtained on oral administration in rats of the compounds of FormulaI in the anti-secretory and the reserpine-induced anti-ulcer tests aregiven in terms of the % increase in the pH of gastric fluid over controlanimals and the % reduction in ulcer score over control animals. Dosesare expressed in mg./kg., and the compounds are identified by theExample number above where they are disclosed.

    ______________________________________                                        Example                                                                              Dose    % pH Increase                                                                             % Reduction Ulcer Score                            ______________________________________                                        20     25      9           60                                                        50      50          60                                                        100     84          100                                                       200     96          100                                                20A            Inactive    Inactive                                           20B    100     20          40                                                 20C    100     24          0                                                  20D    100     7           0                                                  20E    100     4           0                                                  20F    12.5    41          --                                                        25      52          73                                                        50      75          100                                                       100     100         100                                                20G    25      --          40                                                        50      55          60                                                        100     93          --                                                        100     95          100                                                20H    25      56          60                                                        50      80          100                                                       100     93          100                                                20J    100     4           60                                                 20K    25      --          100                                                       50      --          100                                                       100     46          100                                                       200     49          --                                                 20L    100     10          0                                                  20M    100     16          0                                                  20N    100     35          70                                                 20P    100     45          100                                                20Q    100     20          80                                                 20R    100     16          0                                                  20S    100     27          0                                                  20T    50      --          80                                                        100     47          90                                                 20U    100     9           0                                                  20V    25      --          80                                                        50      32          100                                                       100     45          --                                                        100     64          100                                                20W    100     20          20                                                 20X    100     5           0                                                  20Y    100     145         100                                                20Z    100     77          40                                                 20AA   100     26          40                                                 20AB   100     18          0                                                  20AC   100     4           0                                                  20AD   25      3           --                                                        50      11          --                                                        100     16          0                                                  20AE   50      157         100                                                       100     253         --                                                        200     400         --                                                 20AF   25      --          20                                                        50      20          --                                                        100     21          --                                                 20AG   100     0           20                                                 20AH   100     0           40                                                 20AK   25      48          20                                                        50      110         --                                                        100     120         --                                                 20AL   25      33          --                                                        50      75          100                                                       100     325         --                                                 20AM   100     0           0                                                  20AN   100     14          100                                                20AP   100     54          80                                                 20AQ   50      8           80                                                 20AR   100     10          20                                                 20AS   100     18          0                                                  20AT   100     27          100                                                20AU   100     0           0                                                  20AV   12.5    236         --                                                 20AW   50      --          40                                                        100     68          --                                                 20AX   100     0           0                                                  20AY   50      --          100                                                       100     38          --                                                 20AZ   100     38          40                                                 20BA   100     0           20                                                 20BB   100     0           20                                                 22     100     72          100                                                24     100     15          0                                                  26     100     8           60                                                 26A    12.5    45          --                                                        25      228         --                                                        50      445         --                                                        100     480         --                                                 26B    12.5    0           60                                                        25      8           80                                                        50      163         --                                                        100     399         --                                                 26C    100     14          20                                                 26D    100     0           60                                                 26E    100     42          0                                                  26F    25      0           --                                                        50      79          80                                                        100     244         --                                                 26G    100     18          --                                                 26H    12.5    0           --                                                        25      45          --                                                        50      118         --                                                        100     355         --                                                 27     50      0           --                                                        100     --          0                                                  28     50      10          100                                                       100     140         --                                                 30     100     17          0                                                  32     50      --          0                                                         100     16          80                                                 34     100     0           80                                                 35     100     51          75                                                 36     50      0           --                                                        100     11          --                                                 37     100     188         --                                                 38     100     27          40                                                 38A    100     73          100                                                38B    100     336         --                                                 39     25      --          80                                                        50      128         --                                                        100     166         --                                                        200     530         --                                                 40     12.5    31          --                                                        25      289         --                                                        50      565         --                                                        100     580         --                                                 40A    100     16          --                                                 40B    100     0           --                                                 40C    25      7           --                                                        50      587         --                                                        100     600         --                                                 40D    100     8           --                                                 40E    100     4           --                                                 40F    100     24          --                                                 40G    100     14          --                                                 40H    25      32          --                                                        50      116         --                                                        100     458         --                                                 ______________________________________                                    

We claim:
 1. A compound having the formula ##STR28## where each of R₃,R₄ and R₅ is hydrogen or methyl; each R₆ group is the same or differenthydrogen, formyl, and lower-alkane-1,3-diol ketals thereof,phenyl-lower-alkyl, carboxy, carbo-lower-alkoxy, chloromethyl,dichloromethyl, trichloromethyl, hydroxymethyl, hydroxycyanomethyl orlower-alkyl; and R₇ is di-lower-alkylamino-lower-alkyl, and wherein saidlower-alkane, lower-alkyl and lower-alkoxy groups, all occurrences, havefrom one to four carbon atoms.
 2. A compound having the formula##STR29## where each of R₃, R₄ and R₅ is hydrogen or methyl; each R₆group is the same or different hydrogen, formyl, andlower-alkane-1,3-diol ketals thereof, hydroxymethyl, carboxy,carbo-lower-alkoxy, chloromethyl, dichloromethyl, trichloromethyl,hydroxycyanomethyl or lower-alkyl; and R₇ isdi-lower-alkylamino-lower-alkyl, and wherein said lower-alkanelower-alkyl and lower-alkoxy groups, all occurrences, have from one tofour carbon atoms.
 3. A compound according to claim 2 having the formula##STR30## where each of R₃, R₄ and R₅ is hydrogen or methyl; both R₆groups are simultaneously lower-alkyl; and R₇ isdi-lower-alkylamino-lower-alkyl. 4.2-[3-(Dimethylamino)propyl]-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrileaccording to claim
 3. 5.2-(2-Diethylaminoethyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrileaccording to claim 3.